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.

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.).

Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD). METHODS: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8-17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression. RESULTS: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4-2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9-6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8-7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0-3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data. CONCLUSIONS: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.

Accuracy and Performance of Triage Blood Pressure Measurements in A Real-World Clinic Setting.

OBJECTIVES: To investigate the agreement and accuracy of triage blood pressure (BP) in a real-world clinic setting, compared with the reference standard. STUDY DESIGN: Paired triage and standardized BP measurements from patients 4 through 21 years old evaluated in an obesity-related hypertension clinic were obtained via chart-review. Triage BPs were measured by a medical assistant or nurse, often by automated device. Triplicate manual BPs were obtained by the clinic physician. Bland-Altman analyses determined mean differences between paired triage and mean standardized BPs. GEE-based multivariable relative risk (RR) regression determined the RR of triage BP overestimation by ≥ 5 mmHg. Overall agreement, sensitivity, specificity, positive predictive value, and negative predictive value of triage BP measurements identifying hypertensive BP were determined. RESULTS: One hundred thirty participants with 347 clinic encounters were included. Mean age was 13.3 years (SD 3.94), 76% were Black, and 58% were male. Overall mean systolic and diastolic BP difference was 8.7 mmHg (95% limits on agreement: -16.66, 34.07) and 4.1 mmHg (95% limits on agreement: -18.56, 26.68), respectively. Triage systolic BP was more likely overestimated by ≥ 5 mmHg when a large adult (RR = 1.49; 95% CI: 1.00, 2.21) or thigh cuff (RR = 1.94; 95% CI: 1.08, 3.51) was required compared with when a child/adult cuff was required. Overall agreement in identifying hypertensive BP was 57.6%. Sensitivity (52.6%), specificity (63.4%), positive predictive value (60.8%), and negative predictive value (55.3%) were low across all cuffs. CONCLUSIONS: There was poor agreement between usual triage and standardized BP measurements, with potential for significant clinical implications. CLINICAL TRIAL REGISTRATION: ReNEW Clinic Cohort Study (ReNEW), NCT03816462, https://clinicaltrials.gov/ct2/show/NCT03816462.

Pediatric Blood Pressure and Cardiovascular Health in Adulthood.

PURPOSE OF REVIEW: This review summarizes current knowledge on blood pressure in children and adolescents (youth), with a focus on primary hypertension-the most common form of elevated blood pressure in this demographic. We examine its etiology, progression, and long-term cardiovascular implications. The review covers definitions and recommendations of blood pressure classifications, recent developments in measurement, epidemiological trends, findings from observational and clinical studies, and prevention and treatment, while identifying gaps in understanding and suggesting future research directions. RECENT FINDINGS: Youth hypertension is an escalating global issue, with regional and national variations in prevalence. While the principles of blood pressure measurement have remained largely consistent, challenges in this age group include a scarcity of automated devices that have passed independent validation for accuracy and a generally limited tolerance for ambulatory blood pressure monitoring. A multifaceted interplay of factors contributes to youth hypertension, impacting long-term cardiovascular health. Recent studies, including meta-analysis and sophisticated life-course modelling, reveal an adverse link between youth and life-course blood pressure and subclinical cardiovascular outcomes later in life. New evidence now provides the strongest evidence yet linking youth blood pressure with clinical cardiovascular events in adulthood. Some clinical trials have expanded our understanding of the safety and efficacy of antihypertensive medications in youth, but this remains an area that requires additional attention, particularly regarding varied screening approaches. This review outlines the potential role of preventing and managing blood pressure in youth to reduce future cardiovascular risk. A global perspective is necessary in formulating blood pressure definitions and strategies, considering the specific needs and circumstances in low- and middle-income countries compared to high-income countries.

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.

Association of Childhood Blood Pressure with Left Atrial Size and Function: Study of High Blood Pressure in Pediatrics-Adult Hypertension in Youth (SHIP AHOY).

OBJECTIVE(S): To evaluate the cross-sectional association of cardiovascular disease risk factors with left atrial (LA) size and function among healthy youth, aged 11-18 years, with a wide range of blood pressures (BPs). STUDY DESIGN: Echocardiographic images of youth enrolled in the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth study were analyzed for LA measurements. The association of casual BP, ambulatory BP, and other cardiovascular disease risk factors with LA size and function were determined using descriptive statistics and multivariable regression. Regression models adjusting for age, sex, race, and body mass index z score determined the independent association between ambulatory systolic BP indices (mean systolic BP/50th %ile systolic BP) and BP phenotypes with LA outcomes while exploratory analyses investigated for additional predictors of LA outcomes. RESULTS: The study population consisted of 347 youth: median age 15.7 years, 60% male and 40% non-White. Greater-risk casual systolic BP groups had worse cardiometabolic profiles but no differences in LA size and function. Each 0.1 increase in ambulatory systolic BP day or night index was associated with a 9.9 mL/m2 increase in LA volume/body surface area (LAV/BSA; 95th% CI 2.8-17.0, P = .006) and a 6.8 mL/m2 increase in LAV/BSA (95th% CI 0.8-12.8, P = .03), respectively. Ambulatory hypertension was associated with greater odds of abnormal LAV/BSA, defined as >75th %ile (2014 ambulatory BP monitoring criteria: OR 3.2 [95th% CI 1.4-7.2; P = .002]; 2022 ambulatory BP monitoring criteria: OR 2.1 [95th% CI 1.0-4.1; P = .008]). CONCLUSIONS: Increasing ambulatory systolic BP and ambulatory hypertension are independently associated with LAV/BSA.

Is There a Role for Imaging Youth at Risk of Atherosclerosis?

PURPOSE OF REVIEW: Cardiovascular (CV) risk factors such as dyslipidemia, hypertension, diabetes, and obesity are associated with an increased risk for CV events in adults. Noninvasive measures of vascular health are associated with these CV events and can potentially help risk stratify children with CV risk factors. The purpose of this review is to summarize recent literature regarding vascular health in children with cardiovascular risk factors. RECENT FINDINGS: Adverse changes in pulse wave velocity, pulse wave analysis, arterial distensibility, and carotid intima-media thickness are seen in children with CV risk factors supporting potential utility in risk stratification. Assessing vascular health in children can be challenging due to growth-related changes in vasculature, multiple assessment modalities, and differences in normative data. Vascular health assessment in children with cardiovascular risk factors can be a valuable tool for risk stratification and help identify opportunities for early intervention. Future areas of research include increasing normative data, improving conversion of data between different modalities, and increasing longitudinal studies in children linking childhood risk factors to adult CV outcomes.

Diabetes complications and cognitive function in young adults with youth-onset type 1 or type 2 diabetes: the SEARCH for Diabetes in Youth Study.

Aims/hypotheses: People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods: Using data from the SEARCH for Diabetes in Youth study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D=646; T2D=165). A three-cluster(C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results: The average age-corrected score for composite fluid cognition differed significantly across clusters for each group (p<0.001). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/interpretations: These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

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.

Prevalence Implications of the 2017 American Academy of Pediatrics Hypertension Guideline and Associations with Adult Hypertension.

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.

Lipids: a Potential Molecular Pathway Towards Diastolic Dysfunction in Youth-Onset Type 2 Diabetes.

PURPOSE OF THE REVIEW: Obesity and type 2 diabetes (T2D) with onset in youth are emerging public health concerns. Youth with obesity and T2D are at risk for the development of heart failure with preserved ejection fraction (HFpEF) due to diabetes-related cardiomyopathy with evidence of precursor stages, namely diastolic dysfunction, present in youth. We review the literature regarding diastolic dysfunction in youth with obesity and T2D; discuss the potential mechanisms including the role of lipids, contractile proteins and their post-translational modifications, and conclude with studies to guide future treatments. RECENT FINDINGS: The diabetes milieu namely hyperglycemia, hyperinsulinemia, and lipotoxicity favor development of diastolic dysfunction and HFpEF. Recent studies show HFpEF is associated with slow left ventricular relaxation and sarcomere stiffness induced by reduced calcium (Ca2+) and ß-adrenergic responses. There are currently no effective therapies available for treating HFpEF. Targeting the sarcomere is an area of ongoing research.

Obese and Type 2 Diabetic Youth Have Increased Forward and Backward Wave Reflections.

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.

EKG Abnormalities in a Youth Athlete Following COVID-19: It's Not Always Myocarditis!

COVID-19 associated myocarditis following mild infections is rare while incidental findings may be more common. A young athlete fully recovered from a mild COVID-19 infection presented with inferolateral T-wave inversions and left ventricular hypertrophy on imaging. Exercise testing aided in correctly diagnosing the patient with masked systolic hypertension.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Early Atherosclerotic Inflammatory Pathways in Children with Obstructive Sleep Apnea.

OBJECTIVE: To evaluate structural and functional carotid changes and inflammatory profiles in children with obstructive sleep apnea (OSA) and healthy controls. STUDY DESIGN: Patients with OSA and matched controls (ages 5-13 years) were recruited. Proinflammatory cytokines and acute phase reactants were measured at 6:00 p.m. Common carotid artery measures were determined using ultrasound. Confirmatory factor analysis was used to determine subgroups of cytokines and their effects on carotid measures. RESULTS: Ninety-six patients participated (53 healthy controls, 43 patients with OSA). OSA was associated with increased proinflammatory cytokines (cluster of differentiation-40 ligand [CD40-L], interleukin [IL]-6, and IL-8) and high sensitivity C-reactive protein (P < .05 for all). One cytokine subgroup (IL-6 and IL-8) was negatively associated with markers of carotid function, indicating reduced arterial distensibility and increased stiffness (P < .05 for 3 ultrasound measures); and tumor necrosis factor-α had an opposing effect on carotid function compared with this cytokine subgroup (P < .05 for 2 ultrasound measures). Linear regression demonstrated significant associations between and tumor necrosis factor- α and 2 measures of carotid function (P < .05 for each). Children with OSA did not have functional or structural carotid changes compared with controls. CONCLUSION: OSA was not directly associated with structural and functional carotid changes but was associated with upregulation of key proinflammatory cytokines (sCD40-L, IL-6, and IL-8). Together, IL-6 and IL-8 were associated with changes in carotid function. Longitudinal studies are needed to demonstrate that the inflammatory milieu observed in our population is a precursor of atherosclerosis in children.

Left Ventricular Diastolic Dysfunction Among Youth with Obesity and History of Elevated Blood Pressure.

OBJECTIVE: To assess prevalence of and factors associated with left ventricular diastolic dysfunction (LVDD) in youth with obesity and elevated blood pressure (BP). STUDY DESIGN: This was a cross-sectional analysis of baseline and follow-up visits of 83 youth, 5-21 years, evaluated for overweight/obesity and elevated BP in a multidisciplinary clinic. LVDD was defined according to established adult criteria (LVDDadult; E/A < 1, E/e' > 14, or e'/a' < 0.8) and pediatric criteria (LVDDpeds; E/A <10th percentile, E/e' >99th percentile, or e'/a' <1st percentile) based on data from 103 age-sex matched healthy controls. Baseline factors associated with LVDDpeds were examined using Wilcoxon rank sum and χ2 tests. Multiple logistic regression analyses using generalized estimating equations to account for repeated measures evaluated the associations of adiposity and BP with LVDDpeds. RESULTS: The prevalence of LVDD ranged from 1.2% to 2.7% when we used adult criteria and 19% to 28% when we used pediatric criteria. Those with LVDDpeds were older, predominantly male, and non-African American and had greater weight, BP, BP medication use, and non-high-density lipoprotein cholesterol than those without LVDDpeds. Diastolic BP z score was associated with LVDDpeds by E/A (OR 1.95, 95% CI 1.15-3.32, P = .014) after we adjusted for age, sex, race, BP medications, and body mass index z score. CONCLUSIONS: LVDD was present in a substantial proportion of youth with overweight/obesity and elevated BP using pediatric criteria. Those with LVDDpeds had significantly greater measures of adiposity and BP compared with those without LVDDpeds, and diastolic BP z score was an independent predictor of LVDDpeds by E/A. These data emphasize the importance of prevention and treatment of cardiovascular disease risk factors in childhood.

A cross sectional study to compare cardiac structure and diastolic function in adolescents and young adults with youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study.

AIMS: To compare left ventricular structure (LV) and diastolic function in young adults with youth- onset diabetes by type, determine the prevalence of abnormal diastolic function by diabetes type using published values from age similar healthy controls, and examine the risk factors associated with diastolic function. METHODS: In a cross sectional analysis we compared LV structure and diastolic function from two dimensional echocardiogram in participants with type 1 (T1D) and type 2 diabetes (T2D) who participated in the SEARCH for Diabetes in Youth Study. Linear models were used to examine the risk factors associated with worse diastolic function. RESULTS: Of 479 participants studied, 258 had T1D (mean age 21.2 ± 5.2 years, 60.5% non-Hispanic white, 53.9% female) and 221 had T2D (mean age 24.8 ± 4.3 years, 24.4% non-Hispanic white, 73.8% female). Median diabetes duration was 11.6 years. Participants with T2D had greater LV mass index and worse diastolic function that persisted after adjustment for differences in risk factors compared with participants with T1D (all p < 0.05). Abnormal diastolic function, quantified using healthy controls, was pronounced in both groups but greater in those with T2D than T1D (T2D: 57.7% vs T1D: 47.2%, respectively), p < 0.05. Risk factors associated with worse diastolic function included older age at diabetes diagnosis, female sex, higher BP, heart rate and HbA1c and longer diabetes duration. CONCLUSIONS: LV structure and diastolic function is worse in individuals with T2D compared to T1D. However, abnormal diastolic function in seen in both groups compared to published values from age similar healthy controls.

Glycemic control is associated with dyslipidemia over time in youth with type 2 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Dyslipidemia has been documented in youth with type 2 diabetes. There is a paucity of studies examining dyslipidemia over time in youth with type 2 diabetes and associated risk factors. OBJECTIVE: To evaluate lipids at baseline and follow-up and associated risk factors in youth with type 2 diabetes. METHODS: We studied 212 youth with type 2 diabetes at baseline and after an average of 7 years of follow-up in the SEARCH for Diabetes in Youth Study. Abnormal lipids were defined as high-density lipoprotein cholesterol (HDL-C) < 35, low-density lipoprotein cholesterol (LDL-C) > 100, or triglycerides >150 (all mg/dl). We evaluated participants for progression to abnormal lipids (normal lipids at baseline and abnormal at follow-up), regression (abnormal lipids at baseline and normal at follow-up), stable normal, and stable abnormal lipids over time for HDL-C, LDL-C, and triglycerides. Associations between hemoglobin A1c (HbA1c) and adiposity over time (area under the curve [AUC]) with progression and stable abnormal lipids were evaluated. RESULTS: HDL-C progressed, regressed, was stable normal, and stable abnormal in 12.3%, 11.3%, 62.3%, and 14.2% of participants, respectively. Corresponding LDL-C percentages were 15.6%, 12.7%, 42.9%, and 28.8% and triglycerides were 17.5%, 10.8%, 55.7%, and 16.0%. Each 1% increase in HbA1c AUC was associated with a 13% higher risk of progression and stable abnormal triglycerides and a 20% higher risk of progression and stable abnormal LDL-C. Higher adiposity AUC was marginally (p = 0.049) associated with abnormal HDL-C. CONCLUSIONS: Progression and stable abnormal LDL-C and triglycerides occur in youth with type 2 diabetes and are associated with higher HbA1c.

Cardiovascular risk factors before and during pregnancy: Does pregnancy unmask or initiate risk?

OBJECTIVES: To understand if pregnancy unmasks previously silent cardiovascular (CV) adverse factors, or initiates lasting injury. METHODS: Pre-pregnancy and during pregnancy CV risk factors (blood pressure, fasting lipids, and glucose) from 296 women belonging to studies in the International Childhood Cardiovascular Cohort (i3C) Consortium, a group of studies assessing the relationship between child and adolescent CV risk factors and adult outcomes, were used. Correlation coefficients between the pre- and during pregnancy measures were calculated, and the mean difference between the measures was modeled with adjustment for age, body mass index, race, smoking, and study. RESULTS: Measures were strongly correlated at pre- and during-pregnancy visits (p < 0.01), with r of between 0.30 and 0.55. In most cases, the difference between pre-pregnancy and during-pregnancy did not differ significantly from 0 after adjustment for confounders. Stratification by gestational age indicated stronger correlations with measurements obtained during the first and second trimesters than the third. The correlation did not differ by the time elapsed between the pre-pregnancy and pregnancy visits. CONCLUSIONS: Pre- and during-pregnancy CV risk factors are moderately well correlated. This may indicate that susceptible women enter pregnancy with higher risk rather than pregnancy inducing new vascular or metabolic effects.