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Background: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)–related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. Methods: Participants were stratified by systolic BP into low- (systolic BP Results: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. Conclusions: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

Background Mortality in cohorts with a single ventricle remains high with multiple associated factors. The effect of heart block during stage I palliation remains unclear. Objective The purpose of this study was to study patient and surgical risks of heart block and its effect on 12-month transplant-free survival in patients with a single ventricle. Methods Patient, surgical, outcome data and heart block status (transient and permanent) were obtained from the National Pediatric Cardiology Quality Improvement Collaborative single ventricle database. Bivariate analysis was performed comparing patients with and without heart block, and multivariate modeling was used to identify variables associated with block. One-year outcomes were analyzed to identify variables associated with lower 12-month transplant-free survival. Results In total, 1423 patients were identified, of whom 28 (2%) developed heart block (second degree or complete) during their surgical admission. Associated risk factors for block included heterotaxy syndrome (odds ratio [OR] 6.4) and atrial flutter/fibrillation (OR 3.8). Patients with heart block had lower 12-month survival, though only in patients with complete heart block as opposed to second degree block. At 12 months of age, 43% (12/28) of patients with heart block died and were more likely to experience mortality at 12 months than patients without block (OR 4.9; 95% confidence interval 1.4–17.5; P = .01). Conclusion Although rare, complete heart block after stage I palliation represents an additional risk of poor outcomes in this high-risk patient population. Heterotaxy syndrome was the most significant risk factor for the development of heart block after stage I palliation. The role of transient block in outcomes and potential rescue with long-term pacing remains unknown and requires additional study.

OBJECTIVE The aim of this study was to examine the association of sodium intake (g/day) and sodium load (Na-L; mg/kcal/day) on arterial stiffness in youth. METHODS A cross-sectional analysis of 723 youth enrolled in a study evaluating the cardiovascular effects of obesity and type 2 diabetes mellitus (T2DM). Three measures of arterial stiffness were evaluated: brachial distensibility (BrachD), carotid-femoral pulse wave velocity (PWVcf) and augmentation index (AIx). Three-day diet histories yielded mean daily sodium and calorie intake. Youth were divided into Na-L tertiles: Low (≤1.67 mg/kcal per day); Medium (1.68--1.98 mg/kcal per day) and High (>1.98 mg/kcal per day). General linear models adjusting for demographics, % body fat, T2DM and SBP z-score evaluated the independent association of Na-L with arterial stiffness. RESULTS Mean age was 17.9 years (10-24 years), 35% male, 59% nonwhite and 31% T2DM. Mean (±standard deviation) dietary intake was calories = 2074 (±797) kcal/day; Na = 3.793 (±1567) g/day; Na- = 1.86 (±0.753) mg/kcal per day. With higher levels of dietary Na intake and Na-L, measures of arterial stiffness worsened: BrachD decreased (Na intake: beta = -0.09, P = 0.003; Na-L: beta = -0.28, P

Background There is little information about how diet quality evolves in early childhood, whether children exhibit varying diet quality trajectories, or which components of diet quality should be targeted for intervention. Objective The goal of this study was to identify and evaluate trajectories of dietary quality in young children. Design This was a secondary analysis of an observational, longitudinal cohort study of non-Hispanic African American or White children and their parents from racially concordant households with 4 years of follow-up (up to 13 study visits). Data on mother, infant feeding, and body mass index were assessed at baseline. Diet was evaluated using 3-day diaries at each visit. Participants/setting Of 372 children enrolled, 349 children had at least 3 study visits with dietary data for this analysis. Participants were enrolled at age 3 years between March 2001 and August 2002 in Cincinnati, OH. Final study visits were conducted between February 2005 and June 2006. Main outcome measure The main outcome measure was the total Healthy Eating Index 2005 (HEI-2005) score and HEI-2005 component scores. Statistical analyses Diet quality trajectories were modeled using group-based modeling techniques. Results The total HEI-2005 score was low at age 3 years (mean ± standard error = 55.1 ± 0.4 of maximum 100 points) and remained stable to age 7 years (mean ± standard error = 54.0 ± 0.6; P = 0.08 for trend). Five HEI-2005 trajectory groups were identified, of which 1 declined and 1 improved over time. HEI-2005 component scores, except milk intake and meat/beans scores, differed significantly (all, P ≤ 0.02) among trajectory groups at age 3 years, and most differences were maintained at age 7 years. Total vegetables, dark green and orange vegetables and legumes, and whole grains component scores were low for all trajectory groups. Whole fruit; total fruit; saturated fat; and calories from solid fats, alcoholic beverages, and added sugars (SoFAAS) were highly variable among trajectory groups. Children in the lowest diet quality trajectory group were less likely to be breastfed and more likely to have been regular consumers of soft drinks (e.g., powdered drink mixes, sport drinks, or soda pop) before age 3 years. Conclusions Young childhood diet quality was low at age 3 years and remained stable to age 7 years. Improving intake of vegetables and whole grains is needed for all children. Focused attention regarding increasing fruit intake and reducing SoFAAS may be needed for families at increased risk for low overall diet quality.

Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF. Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19–32 years) were compared with 20 age-matched healthy volunteers (age range 19–34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations. Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p

Objective: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L ( P ≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values ( P ≤0.05) and near-significant O versus L values ( P =0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e′, and log composite carotid intima-media thickness. Conclusions: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.

Background:Haematopoietic stem cell transplantation is an important and effective treatment strategy for many malignancies, marrow failure syndromes, and immunodeficiencies in children, adolescents, and young adults. Despite advances in supportive care, patients undergoing transplant are at increased risk to develop cardiovascular co-morbidities.Methods:This study was performed as a feasibility study of a rapid cardiac MRI protocol to substitute for echocardiography in the assessment of left ventricular size and function, pericardial effusion, and right ventricular hypertension.Results:A total of 13 patients were enrolled for the study (age 17.5 ± 7.7 years, 77% male, 77% white). Mean study time was 13.2 ± 5.6 minutes for MRI and 18.8 ± 5.7 minutes for echocardiogram (p = 0.064). Correlation between left ventricular ejection fraction by MRI and echocardiogram was good (ICC 0.76; 95% CI 0.47, 0.92). None of the patients had documented right ventricular hypertension. Patients were given a survey regarding their experiences, with the majority both perceiving that the echocardiogram took longer (7/13) and indicating they would prefer the MRI if given a choice (10/13).Conclusion:A rapid cardiac MRI protocol was shown feasible to substitute for echocardiogram in the assessment of key factors prior to or in follow-up after haematopoietic stem cell transplantation.

Arrhythmias are common in single ventricle patients though their effect on outcomes during stage I palliation (S1P) is unclear.The authors sought to study associated risks for arrhythmia in patients undergoing S1P for single ventricle disease and evaluate the outcome of arrhythmias and their treatment strategies on survival.Retrospective patient, surgical, medication, and arrhythmia data were obtained from the NPC-QIC (National Pediatric Cardiology Quality Improvement Collaborative) database. Bivariate analysis of variables associated with arrhythmias, as well as those associated with survival, was performed at the time of stage II palliation. Appropriate variables were included in multivariate modeling.Of the 2,048 patients included in the study, 36% had arrhythmia noted during their S1P hospitalization, with supraventricular tachycardia (12%) and focal atrial tachycardia (11%) the most common. At S1P discharge, 11% of patients were on an antiarrhythmic medication. Arrhythmias were associated with lower survival and increased hospital length of stay. Heterotaxy syndrome, younger age at S1P, male sex, and additional anomalies were associated with increased risk of arrhythmia in multivariable modeling (P ≤ 0.01). Arrhythmia and female sex were associated with increased mortality, whereas antiarrhythmic medication and digoxin use were associated with decreased mortality (P ≤ 0.003, model area under the curve = 0.79). The use of antiarrhythmic medications within the subcohort of arrhythmia patients was also associated with decreased risk of mortality (P lt; 0.0001; odds ratio: 2.0-7.2).Arrhythmias are common during admission for S1P and associated with poor outcomes. The use of antiarrhythmic medications may improve survival, though future studies are needed.

Introduction: Excess visceral fat is implicated in obesity-related cardiometabolic disease, but normal age, sex, and ancestry-related trends in visceral fat among youth with varying body size and metabolic health status are unknown. Objective: The objective of this study was to characterize age, sex, and ancestry-related trends in abdominal visceral fat among youth with healthy weight, obesity, and type 2 diabetes. Methods: This cross-sectional sample included youth ages 10 to 23 years (67% female, 56% non-black) with healthy weight (BMI=5 th to 85 th percentile, n=236), obesity (BMI > 95 th percentile, n=224), and type 2 diabetes (BMI > 95 th percentile, n=145). Visceral fat (cm 2 ) was assessed via dual-energy X-ray absorptiometry. Multiple linear regression analyses were performed to examine interaction and main effects of age, sex, and ancestry in relation to visceral fat (log) in the three groups separately. Results: Age was positively associated with visceral fat in the healthy weight (P Conclusions: This study reports novel findings with respect to demographic determinants of visceral fat assessed via DXA in children, adolescents, and young adults. Our findings that sex differences in visceral fat in youth with obesity and type 2 diabetes persisted following control for BMI are novel and of clinical interest. Specifically, that females may accrue greater visceral adiposity with weight gain when compared to their male counterparts might help to explain differing risk for obesity-related chronic disease. Prospective studies of youth during critical periods of growth are needed to define the consequences of excess visceral fat accrual with respect to future cardiometabolic risk.

Patients with left ventricular noncompaction (LVNC) are at risk of clinically significant arrhythmias and sudden death. We evaluated whether implantable loop recorders could detect significant arrhythmias that might be missed in these patients during annual Holter monitoring. Selected pediatric and adult patients with LVNC who consented to implantable loop recorder placement were monitored for 3 years (study duration, 10 April 2014–9 December 2019). Fourteen subjects were included (age range, 6.5–36.4 yr; 8 males). Of 13 patients who remained after one device extrusion, one underwent implantable cardioverter-defibrillator placement. Four patients (31%) had significant arrhythmias: atrial tachycardia (n=2), nonsustained ventricular tachycardia (n=1), and atrial fibrillation (n=1). All 4 events were clinically asymptomatic and not associated with left ventricular ejection fraction. In addition, a high frequency of benign arrhythmic patterns was detected. Implantable loop recorders enable continuous, long-term detection of important subclinical arrhythmias in selected patients who have LVNC. These devices may prove to be most valuable in patients who have LVNC and moderate or greater ventricular dysfunction.

Vasculopathy has been identified in young individuals with Turner syndrome (TS). No studies in young individuals with TS have investigated whether this vasculopathy progresses over time. The objective of this study is to describe the changes in vasculopathy over time in a cohort of young individuals with TS. Repeat ultrasound and SphygmoCor CPV® (AtCor Medical) measurements of carotid thickness and peripheral arterial stiffness were performed. Vascular measurements were compared at baseline and follow-up. Follow-up measurements were also compared to historical lean (L) and obese (O) age-, race-, and sex-matched non-TS controls. Thirty-five individuals with TS were studied at a mean age of 19.4 years (range, 13.9–27.5). Mean time to follow-up was 7.2 years (range, 7.1–7.8). Carotid intima media thickness increased by 0.03 ± 0.07 mm (p

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder leading to progressive skeletal and cardiac myopathy. Elevated myocardial T1 values correlate with fibrosis in most disease processes, but DMD skeletal and cardiac histopathology is defined by fibrofatty replacement that may result in a decrease in T1 values, due to the low T1 of fat. The study goal was to assess myocardial T1 values in DMD patients with and without late gadolinium enhancement (LGE). A retrospective analysis was performed on all patients with DMD referred for CMR at our institution from 7/5/2017 to 10/24/2018. T1 measurements were performed using breath-held modified Look Locker inversion recovery (MOLLI) sequences at the basal and mid-ventricular levels. The cohort was separated into patients without the presence of LGE (LGE−) and patients with current or previous LGE (LGE+). A total of 207 CMR studies were analyzed. The LGE− group comprised 88 patients while 119 patients were in the LGE+ group. The LGE+ group was older, had larger indexed LV end-diastolic volume and lower LV ejection fraction (LVEF) compared to the LGE− group. T1 values in the LGE+ group were lower compared to the LGE− group (mid T1 1012 ms vs. 1035 ms; p = 0.002), with 5 CMR studies demonstrating mid T1 values

Objective To compare length of stay of the initial neonatal hospitalization and mortality across multiple stages of surgical palliation for infants with left-sided obstructive lesions and severely restrictive or intact atrial septum (I/RAS). Methods Retrospective cohort study of patients prenatally diagnosed with left-sided obstructive lesions and I/RAS, defined by fetal pulmonary venous Dopplers. Results We identified 76 fetal patients with 59 live born intending to pursue intervention. Those with I/RAS had longer durations of mechanical ventilation (P = .031) but no difference in intensive care unit or total length of stay. Survival to discharge from neonatal hospitalization was 41.7% in the I/RAS group and 80.7% in the unrestrictive group (P = .001). There was a higher proportion of deaths between stage 1 and stage 2 in the I/RAS group - 5/9 (55.6%) vs 9/50 (18%) in the unrestrictive group (P = .027). Beyond stage 2 palliation there was trend toward a difference in overall mortality (66.7% in I/RAS vs 35.7% in unrestrictive, P = .05) but no statistically significant difference in transplant-free survival (33.3% in I/RAS vs 53.5% in unrestrictive, P = .11). Conclusion The survival disadvantage conferred by prenatally diagnosed severe atrial septal restriction is most pronounced in the neonatal and early infancy period, with no detectable difference in late midterm transplant-free survival in our cohort.

OBJECTIVE(S): Few data exist relating the burden of cardiovascular (CV) risk factors over the childhood and young adult years on left ventricular mass (LVM), a known risk factor for hard CV events later in life. Racial differences exist in the development of cardiovascular Disease (CVD), with blacks adversely affected. We examined racial differences in the relationship between CV risk factors measured since age 10 and left ventricular mass index (LVMI) in adulthood in the NHLBI Growth and Health Study. STUDY DESIGN: Longitudinal investigation with CV risk factors measured throughout childhood and LVMI measured in adulthood. 556 black and white girls recruited from schools in the greater Cincinnati area. Analyses examined traditional CV risk factors at baseline, follow-up, and over time (i.e. area under the curve, AUC). LVMI was collected with 2-D guided echocardiographic imaging at a mean age of 25.7 ± 1.7 years. RESULTS: Black girls had higher adiposity and insulin and lower heart rate across time (all p < 0.05). Blacks had higher LVMI compared to whites in adulthood. Major determinants of young adult LVMI, were race, body mass index z-score AUC, systolic blood pressure z-score AUC, percent body fat by skin fold AUC, heart rate AUC, and an interaction between race and heart rate (model R(2) = 0.40, p < .0001). CONCLUSIONS: The major determinants of LVMI in young adult females are race, adiposity and systolic blood pressure. The contribution of heart rate to LVMI in whites may relate to previously noted higher sympathetic tone in obese whites.

Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children with a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy (HCM, DCM, or RCM), and to compare disease outcomes between individuals with and without a de novo variant. A retrospective record review identified 126 individuals with HCM (55%), DCM (37%), or RCM (8%) ≤18 years of age who had genetic testing. Overall, 50 (40%) had positive genetic testing and 18% of P/LP variants occurred de novo. The rate of de novo variation in those with RCM (80%) was higher than in those with HCM (9%) or DCM (20%). There was evidence of germline mosaicism in one family with RCM. Individuals with de novo variants were more likely than those without to have a history of arrhythmia (p = .049), sudden cardiac arrest (p = .024), hospitalization (p = .041), and cardiac transplantation (p = .030). The likelihood of de novo variation and impact on family risk and screening should be integrated into genetic counseling.

Background: Increased arterial stiffness is associated with diastolic dysfunction in adults. Data in youth are lacking, so we examined the impact of arterial stiffness on diastolic function in youth.Methods: We obtained diastolic function and augmentation index, pulse wave velocity, brachial artery distensibility, and carotid stiffness on 612 youth [10–24 years, 65% female, 38% normal weight, 36% obese, and 26% with type 2 diabetes mellitus (T2DM)]. Participants were classified as compliant (C) vs. stiff (S) arteries based on seven arterial stiffness parameters [Global Stiffness Index (GSI), S = GSI > 4). Mean differences in covariates were evaluated by Student's t-tests. A stepwise regression analysis was performed to determine if GSI was an independent predictor of diastolic function.Results: Lower diastolic function and more adverse cardiovascular disease (CVD) risk factors were present in the S group (n = 67) than the C group (n = 545) (p < 0.001). Covariates that were associated with diastolic dysfunction were higher GSI, male sex, higher body mass index (BMI), and systolic blood pressure (SBP) z-score (R2 = 0.18 to 0.25; p ≤ 0.05).Conclusion: Adverse diastolic function is seen in youth with increased arterial stiffness independent of CVD risk factors. Interventions to improve arterial stiffness prior to clinical onset of diastolic dysfunction are needed to prevent development of heart failure.

Objective: To evaluate the impact of the 2017 American Academy of Pediatrics hypertension Clinical Practice Guideline (CPG), compared with the previous guideline (“Fourth Report”), on the frequency of hypertensive blood pressure (BP) measurements in childhood and associations with hypertension in adulthood using data from the International Childhood Cardiovascular Cohort Consortium. Study design: Childhood BPs were categorized in normal, prehypertensive/elevated, and hypertensive (stage 1 and 2) ranges using the Fourth Report and the CPG. Participants were contacted in adulthood to assess self-reported hypertension. The associations between childhood hypertensive range BPs and self-reported adult hypertension were evaluated. Results: Data were available for 34 014 youth (10.4 ± 3.1 years, 50.6% female) with 92 751 BP assessments. Compared with the Fourth Report, the CPG increased hypertensive readings from 7.6% to 13.5% and from 1.3% to 2.5% for stage 1 and 2 hypertensive range, respectively (P < .0001). Of 12 761 adults (48.8 ± 7.9 years, 43% male), 3839 (30.1%) had self-reported hypertension. The sensitivity for predicting adult hypertension among those with hypertensive range BPs at any point in childhood, as defined by the Fourth Report and the CPG, respectively, was 13.4% and 22.4% (specificity 92.3% and 85.9%, P < .001), with no significant impact on positive and negative predictive values. Associations with self-reported adult hypertension were similar and weak (c-statistic range 0.61-0.68) for hypertensive range BPs as defined by the Fourth Report and CPG. Conclusions: The CPG significantly increased the prevalence of childhood BPs in hypertensive ranges and improved the sensitivity, without an overall strengthened association, of predicting self-reported adult hypertension.

BACKGROUND AND OBJECTIVES Visceral fat is associated with increased cardiovascular risk in adults, but studies in youth are limited. We assessed associations between visceral fat and arterial stiffness in youth with healthy weight, obesity and type 2 diabetes and determined whether relationships were independent of clinical estimates of body fatness. METHODS This cross-sectional sample included youth ages 10-23 years (67% female, 56% non-black) with healthy weight (body mass index [BMI] = 5th-85th percentile, n = 236), obesity (BMI ≥ 95th percentile, n = 224) and type 2 diabetes (BMI ≥ 95th percentile, n = 145). Visceral fat was assessed via dual-energy X-ray absorptiometry. Carotid-femoral pulse wave velocity (PWV) was assessed via applanation tonometry. Obesity and type 2 diabetes groups were combined for final analyses. Analyses accounted for age, sex, ancestry and mean arterial pressure. RESULTS Visceral fat and PWV were greater in youth with obesity versus healthy weight (p

Background Patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy because of a dystrophin deficiency causing fibrofatty replacement of the myocardium. Corticosteroid use and mobility limitations place these patients at risk for increased adiposity. We sought to determine the association of adiposity with cardiovascular dysfunction in patients with DMD. Methods and Results This was a retrospective review of patients with DMD who underwent both cardiac magnetic resonance imaging and dual‐energy x‐ray absorptiometry within 1 year. The cardiac magnetic resonance imaging parameters included left ventricular ejection fraction and the presence of late gadolinium enhancement (LGE positive [LGE+]). The adiposity indices, measured by dual‐energy x‐ray absorptiometry, included percentage of body fat, whole body fat mass indexed to height, and body mass index. A total of 324 patients were identified. Fifty‐two percent had LGE+, and 36% had cardiac dysfunction (left ventricular ejection fraction P =0.001; and +1.5 kg/m 2 , P =0.03, respectively). whole body fat mass indexed to height remained independently associated with cardiac dysfunction on multivariable analysis after adjusting for age, LGE+, and corticosteroid duration. High whole body fat mass indexed to height and percentage of body fat were associated with LGE+ on univariate analysis (mean difference between patients with and without LGE+: +2.0 kg/m, P =0.02; and +2.4%, P =0.02, respectively). Using multivariable analysis, including age and cardiac dysfunction, high percentage of body fat remained independently associated with LGE+. Conclusions This study demonstrates an independent association of adiposity with cardiac dysfunction and LGE+ in patients with DMD. Preventing adiposity may mitigate the later development of ventricular dysfunction in DMD.

We investigated whether blood pressure (BP) phenotype based on clinic & 24-hour ambulatory BP (ABP) was associated with intermediate markers of cardiovascular disease (CVD) in 374 adolescents enrolled in a study of the relationship of BP to CV risk. Clinic BP was measured by auscultation and categorized using the 2017 AAP guideline. ABP was measured for 24 hours by an oscillometric device and analyzed using the adult ABP wake SBP cut-point (130 mmHg). This created 4 BP phenotype groups: normal BP (n=224), white coat hypertensive (n=48), ambulatory hypertensive (n=57) & masked hypertensive (n=45). Echocardiographic parameters & carotid-femoral pulse wave velocity (PWVcf) were measured to assess CVD risk. Left ventricular mass (LVM) was lowest in the normal BP group, whereas multiple measures of cardiac function and PWVcf were worse in the masked and ambulatory hypertensive groups: Generalized linear models adjusted for body mass index (BMI) were constructed to examine the associations between BP phenotype and the measured CVD variables. ABP phenotype was an independent predictor of LVM, diastolic and systolic function and PWVcf in the unadjusted model. ABP phenotype remained significantly associated with diastolic function (E/e’, e’/a’), systolic function (ejection fraction) and increased arterial stiffness (PWVcf) after adjustment for BMI percentile (all p

Purpose: To assess relationships between diet quality and areal bone mineral density (aBMD) in youth with healthy weight, obesity, and type 2 diabetes (T2D). Methods: We performed a secondary analysis of cross-sectional data from youth (55% African American, 70% female) ages 10–23 years with T2D (n = 90), obesity (BMI &gt, 95th, n = 128), or healthy weight (BMI &lt, 85th, n = 197). Whole body (less head) areal bone mineral density (aBMD) was assessed by dual-energy X-ray absorptiometry (DXA). aBMD was expressed as age-, sex-, and ancestry-specific standard deviation scores (Z-scores). Whole body aBMD Z-scores were adjusted for height-for-age Z-score. Diet was assessed via three-day diaries, and the Healthy Eating Index (HEI) was computed. Total HEI score and HEI subcomponent scores were compared across groups, and associations with aBMD Z-scores were assessed via linear regression adjusted for group, age, sex, and ancestry. Results: Mean HEI was similar between the healthy weight, obesity, and T2D groups. Several HEI sub-components differed between groups, including meats and beans, total vegetables, milk, saturated fat, sodium, oils, and empty calories. The obesity and T2D group had significantly greater aBMD Z-scores compared to the healthy weight group. Multiple linear regression analyses revealed a significant positive association between HEI and aBMD Z-score (p &lt, 0.05). The HEI sub-components for whole grains (p = 0.052) and empty calories (p &lt, 0.05) were positively associated with aBMD Z-score. Conclusions: Individuals that followed a dietary pattern more closely aligned with the Dietary Guidelines for Americans had greater bone density. Since few studies have investigated the role of diet on bone in youth with obesity-related conditions, additional research is required among these populations.

OBJECTIVE Increased carotid intima-media thickness (cIMT) is associated with cardiovascular (CV) events in adults and with elevated CV risk factors in youth. The aim of this study was to determine whether obesity has an direct or indirect association with cIMT. METHODS Structural equation modeling was used to elucidate pathways for obesity to change cIMT. Complete data were collected twice on 294 participants (mean age 17.5 years, 16% with type 2 diabetes). Latent baseline and follow-up cIMT, BMI, and CV risk factors were analyzed with SAS 9.4. Model fit was assessed. RESULTS There were increases in BMI, mean arterial pressure (MAP), low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, C-reactive protein, and glucose and a decrease in insulin and glycosylated hemoglobin over 5 years (all p < 0.05). Only bulb (0.031 mm) and internal (0.027 mm) cIMT increased (all p < 0.001). Significant direct effects on cIMT change were baseline MAP (β 0.23), BMI z score (β 0.16), change in glucose (β 0.37), and age (β 0.37; all p < 0.05). Change in MAP showed a trend (β 0.14, p = 0.10). BMI also had a significant indirect effect (β 0.17), whereas non-HDL demonstrated no significant effect. CONCLUSIONS Baseline adiposity drives increasing blood pressure and glucose in high-risk youth leading to accelerated accumulation of carotid arterial injury. Prevention of acquisition of obesity in youth is critical in slowing development of CV disease.

Left ventricular (LV) mass is a major determining tool for myocardial injury in hypertensive patients. Issues with LV mass calculations exist given that there are multiple methods to assess mass, including from the parasternal long axis (PLA), parasternal short axis (PSA), and 2-dimensional (2D) volumetric methods. The aim of this study was to compare the agreement of LV mass calculations using the PLA, PSA, and 2D volumetric methods. This study retrospectively reviewed 200 consecutive, initial echocardiograms for the indication of hypertension. A single reader calculated the LV mass in each patient via the PLA, PSA, and 2D volumetric methods. Percent differences for each study were calculated. LV mass threshold cutoffs of 51 g/m2.7 (cardiac organ injury) and 38.6 g/m2.7 (elevated LV mass) were used to compare categorical differences between the different measurement methods. Paired comparisons demonstrated an absolute mean percent difference of 8.46% to 9.41% among the different methods. LV mass calculated by the 2D volumetric method was less compared with PLA and PSA methods (31.64 vs 33.90 vs 35.51 g/m2.7; p

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 P P 2

The relationship between single measures of systolic blood pressure (SBP) in youth and adult levels is weak. We sought to define trajectories of SBP over childhood to determine ability to predict adult hypertension (HTN). In the International Childhood CV Cohort (i3C) Consortium, we constructed SBP trajectories in 11,482 participants (mean age 8.0 + 2.0 years at time of first measure, 47% male, 25% non-Caucasian) who had at least 3 SBPs in youth between the ages of 4 and

Background Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction. Methods Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early ( Results Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was − 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was − 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was − 16.2 ± 5.4% vs. -21.6 ± 3.7% (p p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose ( Conclusions Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.

Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF.Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19-32 years) were compared with 20 age-matched healthy volunteers (age range 19-34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations.Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p 0.001 for each comparison). LA conduit:reservoir GLS and pump:reservoir GLS had correlations to native LV T1 (ρ = 0.26, p = 0.03 and ρ = - 0.26, p = 0.03, respectively). LA reservoir SR had positive correlation to RV EF (ρ = 0.27, p = 0.03). There were no statistically significant correlations between LA function and exercise capacity.LA function is altered in adolescent and young adult patients with rTOF indicating worse diastolic function and relates to increasing native LV T1 values. Future studies are indicated to investigate the progression of adverse atrial-ventricular interactions and poor outcomes in this population.

Introduction: Ideal timing for elective delivery of infants with single ventricle heart disease, balancing benefits of fetal growth with risk of fetal demise, remains unclear. Improved understanding of fetal growth in late gestation and postnatal outcomes related to gestational age (GA) may improve insight. Hypothesis: Patients with single ventricle heart disease and aortic hypoplasia have decreased fetal growth velocity in late gestation, but longer gestation results in improved outcomes. Methods: This was a retrospective cohort analysis of patients in phase 2 of the National Pediatric Cardiology Quality Improvement Collaborative database from 2016-2019 who were anticipated to need stage 1 palliation (S1P) and had a GA of > 36 weeks. Birth weight (BW) and BW z-scores were compared across GA to normative values. Outcome measures of survival to stage 2 palliation (S2P), post-S1P length of stay, and duration of mechanical ventilation were compared by GA. Results: The cohort included 1290 infants. There was an increase in mean BW with increasing GA (2.83 kg at 36-37 weeks, 3.15 kg at 38 weeks, 3.33 kg at 39 weeks, 3.40 kg at > 40 weeks; p > 40 weeks; p > 40 weeks; p=0.0001). Among 1083 survivors to discharge or S2P if not discharged, there was no difference in post S1P length of hospitalization across GA (p=0.19). Infants who reached S2P readiness milestones were more likely to undergo S2P if born after longer gestation (p=0.0001). Conclusions: Infants with single ventricle heart disease and aortic hypoplasia have decreased growth velocity in late gestation, but growth continues. Infants born after longer gestation have improved outcomes with shorter duration of ventilation and greater likelihood of undergoing S2P.

This randomized control trial assessed the post-intervention and 18-month follow-up effects of a 6-month dietary approaches to stop hypertension (DASH)-focused behavioral nutrition intervention, initiated in clinic with subsequent telephone and mail contact, on blood pressure (BP) and endothelial function in adolescents with elevated BP. Adolescents (n=159) 11 to 18 years of age with newly diagnosed elevated BP or stage 1 hypertension treated at a hospital-based clinic were randomized. DASH participants received a take-home manual plus 2 face-to-face counseling sessions at baseline and 3 months with a dietitian regarding the DASH diet, 6 monthly mailings, and 8 weekly and then 7 biweekly telephone calls focused on behavioral strategies to promote DASH adherence. Routine care participants received nutrition counseling with a dietitian consistent with pediatric guidelines established by the National High Blood Pressure Education Program. Outcomes, measured pre- and post-intervention and at 18-months follow-up, included change in BP, change in brachial artery flow-mediated dilation, and change in DASH score based on 3-day diet recalls. Adolescents in DASH versus routine care had a greater improvement in systolic BP (–2.7 mm Hg, P = 0.03, –0.3 z-score, P =0.03), flow-mediated dilation (2.5%, P =0.05), and DASH score (13.3 points, P P =0.03) and DASH score (7.4 points, P =0.01) to 18 months. The DASH intervention proved more effective than routine care in initial systolic BP improvement and longer term improvement in endothelial function and diet quality in adolescents with elevated BP and hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00585832.

Background: Early detection of left ventricular (LV) dysfunction before the onset of overt Duchenne muscular dystrophy–associated cardiomyopathy (DMDAC) may direct clinical management to slow onset of dysfunction. We aimed to assess whether LV strain will predict those who develop DMDAC. Methods: We performed a single center retrospective case control study of patients with Duchenne muscular dystrophy who underwent serial cardiac magnetic resonance between 2006 and 2019. Patients with Duchenne muscular dystrophy with an LV ejection fraction ≥55% on ≥1 cardiac magnetic resonance were identified and grouped into age-matched +DMDAC and –DMDAC. Within 3 years, +DMDAC had a subsequent cardiac magnetic resonance with a decline in LV ejection fraction ≥10% and absolute LV ejection fraction ≤50%. −DMDAC maintained an LV ejection fraction ≥55% on serial cardiac magnetic resonances. Two-dimensional and 3-dimensional global radial strain, global circumferential strain (GCS), and global longitudinal strain were measured using tissue tracking software and their ability to predict DMDAC onset was assessed. Multivariable analysis adjusted for late gadolinium enhancement. Results: Thirty +DMDAC and 30 age-matched −DMDAC patients were included with a total of 164 studies analyzed. Before DMDAC onset, 2-dimensional global radial strain and GCS were significantly worse in +DMDAC compared with −DMDAC (25.1±6.0 versus 29.0±6.3, P =0.011; −15.4%±2.4 versus −17.3%±2.6, P =0.003). Three-dimensional GCS and global radial strain had similar findings. Among strain measures, 3-dimensional GCS had the highest area under the curve to predict DMDAC in our cohort. These findings persisted after adjusting for the presence of late gadolinium enhancement. Conclusions: Reduced global radial strain and GCS may predict those at risk for developing DMDAC before onset of LV dysfunction and its clinical utility warrants further exploration.

Background Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM). Objective To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM. Methods We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and β-sitosterol (markers of cholesterol absorption) in the serum of 15-26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls. Results Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and β-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and β-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol. Conclusions Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group. This article is protected by copyright. All rights reserved.

Objective: Youth-onset type 2 diabetes is an aggressive condition with increasing incidence. Adults with type 2 diabetes have increased fracture risk despite normal areal bone mineral density (aBMD), but the influence of diabetes on the growing skeleton is unknown. We compared bone health in youth with type 2 diabetes to controls with obesity or healthy weight. Research Design and Methods: Cross-sectional study of youth (56% African American, 67% female) ages 10-23 years with type 2 diabetes (n=180), obesity (BMI>95th; n=226), or healthy weight (BMIth; n=238). Whole body (less head) aBMD and lean mass, and abdominal visceral fat were assessed via DXA. Lean body mass index (LBMI) and aBMD standard deviation (SD) scores (“Z-scores”) were computed using published reference data. Results: We observed age-dependent differences in aBMD and LBMI Z-scores between the healthy weight, obese, and type 2 diabetes groups. In children, aBMD and LBMI Z-scores were greater in the type 2 diabetes vs obese groups, but in adolescents and young adults, aBMD and LBMI Z-scores were lower in the type 2 diabetes vs. obese group (age interactions P Conclusions: These results suggest that type 2 diabetes may be detrimental to bone density around the age of peak bone mass. Given the increased fracture risk in adults with type 2 diabetes, there is a pressing need for longitudinal studies aimed at understanding the influence of diabetes on the growing skeleton.

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3–18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

Vasculopathy has been identified in young individuals with Turner syndrome (TS). No studies in young individuals with TS have investigated whether this vasculopathy progresses over time. The objective of this study is to describe the changes in vasculopathy over time in a cohort of young individuals with TS. Repeat ultrasound and SphygmoCor CPV® (AtCor Medical) measurements of carotid thickness and peripheral arterial stiffness were performed. Vascular measurements were compared at baseline and follow-up. Follow-up measurements were also compared to historical lean (L) and obese (O) age-, race-, and sex-matched non-TS controls. Thirty-five individuals with TS were studied at a mean age of 19.4 years (range, 13.9-27.5). Mean time to follow-up was 7.2 years (range, 7.1-7.8). Carotid intima media thickness increased by 0.03 ± 0.07 mm (p 0.01) over time, but was less than L and O controls at follow-up. Pulse wave velocity carotid-femoral increased by 0.51 ± 0.86 m/s (p 0.01) over time, but was similar to L and less than O controls at follow-up. Augmentation index (AIx) remained unchanged (p = 0.09) over time, but was significantly higher at follow-up than both control groups (p 0.01 for both). There were no identified differences between 45,X and other TS genotypes. We demonstrate evidence of vascular thickening and stiffening over 7 years in a cohort of young individuals with TS, as well as a persistently increased augmentation index compared to L and O non-TS controls. It is unclear whether the increase in vascular structure and function are related to normal aging or if TS is a risk factor. Higher body mass index seems to be a risk factor. Early estrogen replacement and longer exposure to growth hormone therapy need to be further explored as potential protective factors.

Background Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Whether left ventricular (LV) diastolic function abnormalities related to obesity and T2DM start in adolescence and early adulthood is unknown. We non-invasively evaluated the differences seen in LV diastolic and left atrial (LA) function in adolescents and young adults with obesity and T2DM. Methods We analyzed echocardiographic measures of LV diastolic function in patients with structurally normal hearts which were divided into 3 groups (normal weight, obese, and T2DM). Spectral and tissue Doppler and 2-D speckle tracking measurements of diastolic function were obtained. Logistic regression was performed to compare the prevalence of abnormalities in diastolic function based on the worst 25th percentile for each measure to determine the prevalence of diastolic and LA function abnormalities in obese and T2DM patients. Results 331 teenagers and young adults (median age 22.1 years) were analyzed (101 normal weight, 114 obese, 116 T2DM). Obese and T2DM group had lower E/A and higher E/e′. Obese and T2DM patients had significantly lower atrial reservoir, conduit, and booster strain and worse reservoir and conduit strain rate compared to normal patients (p Conclusions Abnormal indices of LV diastolic function are detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster strain in these patients although LA volume was normal. The use of LA function strain may increase our ability to detect early diastolic function abnormalities in this population.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well‐characterized. We conducted a 5‐year longitudinal study among adolescents with normal‐weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima‐media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid‐femoral pulse wave velocity, and augmentation index). Longitudinal (5‐year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; P P =0.033), internal cIMT (0.03 mm [0.01, 0.05]; P P =0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; P P P P P P P =0.01), internal cIMT (0.008 mm [0.003, 0.013]; P =0.001), and pulse wave velocity carotid‐femoral (0.066 m/sec [0.002, 0.130]; P =0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.

Background: Genome-wide association studies (GWAS) have identified thousands of common genetic variants associated with human height, implicating hundreds of genes and loci. However, the mechanisms by which many of these genetic variants contribute to human adult height are still unknown. Integrating knowledge of the interaction between genetic background and protein levels in childhood can provide insights into the biology of human growth. Objective: To investigate biological associations at height-associated loci in the GH-IGF signaling pathway. Methods: We used data from the Cincinnati Genomic Control Cohort, a community-based cohort comprised of 1,020 children. The study was approved by the institutional review board at Cincinnati Children’s Hospital Medical Center. Protein levels for free and total IGF-I, intact and total IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 were measured by ELISA in 839 children (ages 3-18 years) and corrected for age- and sex-effects. We associated protein-level phenotypes using plink qassoc and stratified by sex and population, in ~870 European- and African-descent individuals. Meta-analyses were performed using the METAL fixed-effects model. GWAS of anthropometric traits were performed in the UK Biobank of ~400,000 individuals using Bolt-LMM, or curated from publicly available summary statistics. Results: We identified 17 independent genome-wide significant protein-level-associated loci (p

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.