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As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had -17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; -22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and -37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases. [ABSTRACT FROM AUTHOR]

Background & Aims: Genome‐wide association studies have identified steatogenic variants that also showed pleiotropic effects on cardiometabolic traits in adults. We investigated the effect of eight previously reported genome‐wide significant steatogenic variants, individually and combined in a weighted genetic risk score (GRS), on liver and cardiometabolic traits, and the predictive ability of the GRS for hepatic steatosis in children and adolescents. Approach & Results: Children and adolescents with overweight (including obesity) from an obesity clinic group (n = 1768) and a population‐based group (n = 1890) were included. Cardiometabolic risk outcomes and genotypes were obtained. Liver fat was quantified using 1H‐MRS in a subset of 727 participants. Variants in PNPLA3, TM6SF2, GPAM and TRIB1 were associated with higher liver fat (p <.05) and with distinct patterns of plasma lipids. The GRS was associated with higher liver fat content, plasma concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST) and favourable plasma lipid levels. The GRS was associated with higher prevalence of hepatic steatosis (defined as liver fat ≥5.0%) (odds ratio per 1‐SD unit: 2.17, p = 9.7E‐10). A prediction model for hepatic steatosis including GRS alone yielded an area under the curve (AUC) of 0.78 (95% CI 0.76–0.81). Combining the GRS with clinical measures (waist‐to‐height ratio [WHtR] SDS, ALT, and HOMA‐IR) increased the AUC up to 0.86 (95% CI 0.84–0.88). Conclusions: The genetic predisposition for liver fat accumulation conferred risk of hepatic steatosis in children and adolescents. The liver fat GRS has potential clinical utility for risk stratification. [ABSTRACT FROM AUTHOR]

Bilirubin is the end product of heme catabolism, mainly produced by the breakdown of mature red blood cells. Due to its anti-inflammatory, antioxidant, antidiabetic, and antilipemic properties, circulating bilirubin concentrations are inversely associated with the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality in adults. Some genetic loci associated with circulating bilirubin concentrations have been identified by genome-wide association studies in adults. We aimed to examine the relationship between circulating bilirubin, cardiometabolic risk factors, and inflammation in children and adolescents and the genetic architecture of plasma bilirubin concentrations. We measured fasting plasma bilirubin, cardiometabolic risk factors, and inflammatory markers in a sample of Danish children and adolescents with overweight or obesity (n = 1530) and in a population-based sample (n = 1820) of Danish children and adolescents. Linear and logistic regression analyses were performed to analyze the associations between bilirubin, cardiometabolic risk factors, and inflammatory markers. A genome-wide association study (GWAS) of fasting plasma concentrations of bilirubin was performed in children and adolescents with overweight or obesity and in a population-based sample. Bilirubin is associated inversely and significantly with a number of cardiometabolic risk factors, including body mass index (BMI) standard deviation scores (SDS), waist circumference, high-sensitivity C-reactive protein (hs-CRP), homeostatic model assessment for insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), triglycerides, and the majority of measured inflammatory markers. In contrast, bilirubin was positively associated with fasting plasma concentrations of alanine transaminase (ALT), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SDS), and the inflammatory markers GH, PTX3, THBS2, TNFRSF9, PGF, PAPPA, GT, CCL23, CX3CL1, SCF, and TRANCE. The GWAS showed that two loci were positively associated with plasma bilirubin concentrations at a p-value threshold of <5 × 10−8 (rs76999922: β = −0.65 SD; p = 4.3 × 10−8, and rs887829: β = 0.78 SD; p = 2.9 × 10−247). Approximately 25% of the variance in plasma bilirubin concentration was explained by rs887829. The rs887829 was not significantly associated with any of the mentioned cardiometabolic risk factors except for hs-CRP. Our findings suggest that plasma concentrations of bilirubin non-causally associates with cardiometabolic risk factors in children and adolescents. [ABSTRACT FROM AUTHOR]

Windkessel function is governed by conductance artery compliance that is associated with cardiovascular disease in adults independently of other risk factors. Sex-related differences in conductance artery compliance partly explain the sex-related differences in risk of cardiovascular disease. Studies on sex-related differences in conductance artery function in prepubertal children are few and inconclusive. This study determined the conductance artery compliance and cardiac function by magnetic resonance imaging in 150 healthy children (75 girls) aged 7-10 yr. Any sex-related difference in conductance artery function was determined with correction for other potential predictors in multivariable linear regression models. Our data showed that ascending [crude mean difference 1.11 95% confidence interval (CI) (0.22; 2.01)] and descending [crude mean difference 1.10 95% CI (0.09; 1.91)] aortic distensibility were higher in girls, but differences disappeared after adjustment for pubertal status and other identified potential predictors. Systolic and diastolic blood pressure, cardiac output, left ventricle (LV) systolic function, and total peripheral resistance did not differ between the sexes. In girls, heart rate was 7 beats/min higher, whereas pulse pressure (by 2 mmHg), LV end-diastolic volume index (by 7 mL), and stroke volume (by 5 mL) were lower. LV peak filling rate indexed to LV end-diastolic volume was 0.5 s-1 higher in girls. In conclusion, prepubertal girls and boys have equal conductance artery function. Thus, the well-known sex difference in adult conductance artery function seems to develop after the onset of puberty with girls initially increasing aortic distensibility. NEW & NOTEWORTHY Although it has been suggested that sex differences in conductance artery function may exist early in childhood, this study demonstrates that the well-known, sex-related difference in conductance artery stiffness (hence Windkessel function) in adulthood is not established before puberty. Thus, healthy prepubertal girls and boys have comparable conductance artery compliance. In contrast to previous studies, our study suggests that pubertal girls develop a more distensible aorta than prepubertal children. [ABSTRACT FROM AUTHOR]

Context: In adults, hyperglucagonemia is associated with type 2 diabetes, impaired glucose tolerance, and obesity. The role of glucagon in pediatric overweight/obesity remains unclear. Objective: We examined whether fasting concentrations of glucagon are elevated in youth with overweight/obesity and whether this associates with cardiometabolic risk profiles. Methods: Analyses were based on the cross-sectional HOLBAEK study, including children and adolescents 6 to 19 years of age, with overweight/ obesity from an obesity clinic group (n = 2154) and with normal weight from a population-based group (n = 1858). Fasting concentrations of plasma glucagon and cardiometabolic risk outcomes were assessed, and multiple linear and logistic regressions models were performed. Results: The obesity clinic group had higher glucagon concentrations than the population-based group (P < 0.001). Glucagon positively associated with body mass index (BMI) standard deviation score (SDS), waist, body fat %, liver fat %, alanine transaminase (ALT), high-sensitivity C-reactive protein, homeostasis model assessment of insulin resistance, insulin, C-peptide, LDL-C, triglycerides, SDS of diastolic and systolic blood pressure, and was inversely associated with fasting glucose. The inverse relationship between glucagon and glucose was attenuated in individuals with high BMI SDS and high fasting insulin. Glucagon was associated with a higher prevalence of insulin resistance, increased ALT, dyslipidemia, and hypertension, but not with hyperglycemia. Glucagon was positively associated with fasting total glucagon-like peptide-1. Conclusion: Compared with normal weight peers, children and adolescents with overweight/obesity had elevated concentrations of fasting glucagon, which corresponded to worsened cardiometabolic risk outcomes, except for hyperglycemia. This suggests hyperglucagonemia in youth may precede impairments in glucose regulation. [ABSTRACT FROM AUTHOR]

Aim: This study investigates the prevalence of disturbed eating behaviours in children and adolescents initiating obesity treatment, and how the prevalence varies with age, sex and body mass index (BMI) standard deviation score (SDS). Secondly, it examines whether the presence of disturbed eating behaviours at enrolment is associated with the degree of weight loss after 12 months of treatment.Methods: A total of 3621 patients aged 3-18 years enrolled in a multidisciplinary obesity treatment programme were studied. Follow-up data after a median of 12.4 months were available for 2055 patients. Upon entry, patients were assessed for the following disturbed eating behaviours: meal skipping, emotional eating, overeating and rapid eating. Height and weight were measured at baseline and follow-up.Results: At enrolment, median age was 11.4 years, median BMI SDS was 2.87, and 82.2% of patients exhibited one or more disturbed eating behaviours. The prevalence of meal skipping, emotional eating and rapid eating increased with age (P < 0.01). Patients who reported overeating or rapid eating exhibited a 0.06-0.11 higher BMI SDS at enrolment than patients without these disturbed eating behaviours (P < 0.02). After 1 year of treatment, BMI SDS was reduced in 75.7% of patients, and the median reduction was 0.24 (95% confidence interval: 0.22-0.27). Overeating was associated with a higher degree of weight loss, while meal skipping, emotional eating and rapid eating did not associate with the degree of weight loss at follow-up.Conclusions: Disturbed eating behaviours were highly prevalent in children and adolescents with overweight or obesity, and varied with age and sex. After 1 year of treatment, the degree of obesity improved, regardless of the presence of disturbed eating behaviours at treatment initiation. [ABSTRACT FROM AUTHOR]

Background: Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood. Objective: This study aims to generate pediatric age and sex‐specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C‐peptide, and homeostasis model assessment: insulin resistance (HOMA‐IR) in Danish/North‐European white children and adolescents from a population‐based cohort and to compare values from children and adolescents with overweight/obesity with this reference. Methods: The population‐ and obesity clinic‐based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age. Anthropometric measurements and blood samples were obtained and percentile curves were calculated. Results: In the population‐based cohort, glucose, insulin, and HOMA‐IR values increased before the expected onset of puberty (P < .05). Thereafter, all variables decreased in girls (P < .05) and HbA1c decreased in boys (P < .05). Concentrations of all measured markers of glucose metabolism were higher in the obesity clinic‐based cohort than the population‐based cohort (both sexes P < .001). Specifically, insulin and HOMA‐IR continued to increase to 18 years in the clinic‐based cohort, particularly among boys. Conclusions: Fasting glucose, insulin, and HOMA‐IR change during childhood, making pediatric reference values essential for timely identification of derangements in glucose metabolism. Children and adolescents with obesity exhibit increased concentrations of these biomarkers. [ABSTRACT FROM AUTHOR]

Background: Cardiac magnetic resonance elastography (MRE) shows promise in assessing the mechanofunctional properties of the heart but faces clinical challenges, mainly synchronization with cardiac cycle, breathing, and external harmonic stimulation., Purpose: To determine the reproducibility of in vivo cardiac multifrequency MRE (MMRE) for assessing diastolic left ventricular (LV) stiffness and viscosity., Study Type: Prospective., Subjects: This single-center study included a total of 28 participants (mean age, 56.6 ± 23.0 years; 16 male) consisting of randomly selected healthy participants (mean age, 44.6 ± 20.1 years; 9 male) and patients with aortic stenosis (mean age, 78.3 ± 3.8 years; 7 male)., Field Strength/sequence: 3 T, 3D multifrequency MRE with a single-shot spin-echo planar imaging sequence., Assessment: Each participant underwent two cardiac MMRE examinations on the same day. Full 3D wave fields were acquired in diastole at frequencies of 80, 90, and 100 Hz during a total of three breath-holds. Shear wave speed (SWS) and penetration rate (PR) were reconstructed as a surrogate for tissue stiffness and inverse viscous loss. Epicardial and endocardial ROIs were manually drawn by two independent readers to segment the LV myocardium., Statistical Tests: Shapiro-Wilk test, Bland-Altman analysis and intraclass correlation coefficient (ICC). P-value <0.05 were considered statistically significant., Results: Bland-Altman analyses and intraclass correlation coefficients (ICC = 0.96 for myocardial stiffness and ICC = 0.93 for viscosity) indicated near-perfect test-retest repeatability among examinations on the same day. The mean SWS for scan and re-scan diastolic LV myocardium were 2.42 ± 0.24 m/s and 2.39 ± 0.23 m/s; the mean PR were 1.24 ± 0.17 m/s and 1.22 ± 0.14 m/s. Inter-reader variability showed good to excellent agreement for myocardial stiffness (ICC = 0.92) and viscosity (ICC = 0.85)., Data Conclusion: Cardiac MMRE is a promising and reproducible method for noninvasive assessment of diastolic LV stiffness and viscosity., Level of Evidence: 2 TECHNICAL EFFICACY: 1., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na + excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14 weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Pediatric obesity associates with both low-grade inflammation and cardiometabolic risk on the population level. Yet on an individual patient level, overweight/obesity does not always equal increased cardiometabolic risk. In this study, we examine whether low-grade inflammation associates with cardiometabolic risk in Danish children, independent of degree of adiposity. We further assess the value of integrating multiple inflammation markers to identify children with very-high cardiometabolic risk profiles., Method and Results: We studied 2192 children and adolescents aged 6-18 years from an obesity clinic cohort and a population-based cohort, in a cross-sectional study design. Anthropometry, blood pressure, pubertal stage and body composition by dual-energy X-ray absorptiometry were assessed, and biomarkers including fasting serum high sensitivity C-reactive protein (hsCRP), white blood cells (WBC), resistin, lipid profile and glucose metabolism were measured. Adjusted correlation analysis and odds ratios were calculated. We found that, independent of degree of adiposity, having high-normal inflammation marker concentrations associated with increased cardiometabolic risk: for girls, hsCRP >0.57-9.98 mg/L (mid/upper tertile) associated with ~2-fold higher odds of dyslipidemia and hepatic steatosis (vs. lower tertile). For both sexes, WBC >7.0-12.4 10 9 /L (upper tertile) associated with 2.5-fold higher odds of insulin resistance. Lastly, children with multiple inflammation markers in the high-normal range exhibited the most severe cardiometabolic risk profile., Conclusion: Low-grade inflammation associates with cardiometabolic risk in children independent of degree of adiposity. The associations vary with sex and inflammation marker measured. Finally, integrating multiple low-grade inflammation markers identifies a very-high-risk subgroup of children with overweight/obesity and may have clinical value., Competing Interests: Declaration of Competing Interest JH received lecture fees from Novo Nordisk and is the owner of Dr Holm Ltd, which provides medical services, training and supervision. All other authors have nothing to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: Oxidative stress may play an important role in childhood obesity and increased cardiometabolic risk. 8-oxo-7,8-dihydroguanosine (8-oxoGuo) from oxidation of RNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) from oxidation of DNA are excreted into urine and function as biomarkers for oxidative stress reflecting the modification rate of nucleic acids by oxidation. This study investigates the associations between urinary markers of nucleic acid oxidation and Body Mass Index (BMI), age, sex and cardiometabolic risk factors in children and adolescents with and without obesity., Methods: We studied 543 children and adolescents from an obesity clinic cohort (n = 418) and a population-based cohort (n = 125), all aged 6-18 years. Anthropometrics, urine and blood samples were collected. A validated liquid chromatography-tandem mass spectrometry method was used to measure the nucleic acid oxidation markers., Results: Compared with the population-based cohort, children and adolescents in the obesity clinic cohort had higher calculated 24-h excretion of 8-oxoGuo (p = 0.045) and 8-oxodG (p = 0.014) adjusted for basal metabolic rate. Both oxidation markers were positively associated with age and female sex (all p < 0.002). In the obesity clinic cohort the RNA oxidation marker 8-oxoGuo correlated with serum insulin (rho = 0.18, p = <.001) and insulin resistance (rho = 0.19, p = <.001)., Conclusions: Childhood obesity associate with higher urinary excretion of nucleic acid oxidation biomarkers, and increase with age throughout childhood, mirroring the obesity- and age-related increase shown in adults. Finally, children with obesity and insulin resistance had higher RNA oxidation markers than children with obesity and no insulin resistance, supporting a possible link between oxidative stress and the pathogenesis of cardiometabolic risk including type 2 diabetes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: It is imperative to develop markers for risk stratification and detection of cardiometabolic comorbidities in children with obesity. The adipokines leptin and adiponectin are both involved in fat mass regulation and the development of obesity-related disorders; furthermore, their ratio (leptin/adiponectin ratio) is suggested to be associated with insulin resistance and cardiometabolic risk., Objective: To evaluate associations between fasting serum concentrations of the adipokines (total leptin and adiponectin as well as the L/A ratio) and cardiometabolic comorbidities in children with overweight/obesity., Methods: A total of 2258 children with overweight/obesity or normal weight aged 6 to 18 years were studied. Differences in anthropometrics and adipokine concentrations were tested using Wilcoxon rank-sum test. Associations between the adipokines and cardiometabolic risk were tested using Spearman's correlation and logistic regression, adjusted for age and body mass index SD score (BMI-SDS)., Results: Compared to normal weight children; children with overweight/obesity exhibited higher leptin concentrations, lower adiponectin concentrations, and higher L/A ratios. After adjusting for age and degree of obesity, girls with overweight/obesity in the upper quartile range for the L/A ratio, when compared with girls in the lower quartile range, were more likely to have insulin resistance (odds ratio [OR]: 7.78 [95% confidence interval [CI], 3.78-16.65]), dysglycemia (OR: 3.08 [95% CI, 1.35-7.31]), and dyslipidemia (OR: 2.53 [95% CI, 1.18-5.59]); while boys were more likely to have insulin resistance (OR: 4.45 [95% CI, 2.03-10.10])., Conclusions: Independent of the degree of obesity, leptin, adiponectin, and the L/A ratio were associated with insulin resistance and other cardiometabolic comorbidities in children with overweight/obesity, but the L/A ratio exhibited stronger associations than the respective adipokines., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Elevated plasma concentrations of liver enzymes are routinely used as markers of liver injury in adults and children. Currently, the age- and sex-specific effects of adiposity on pediatric liver enzyme concentrations are unclear., Methods: We included participants from 2 cohorts of Danish children and adolescents: 1858 from a population-based cohort and 2155 with overweight or obesity, aged from 6 to 18 years. Age- and sex-specific percentile curves were calculated for fasting plasma concentrations of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase (ALP) in both cohorts. Hepatic fat content was assessed by proton magnetic resonance spectroscopy in 458 participants., Results: Concentrations of ALT, AST, LDH, and ALP decreased with age in both girls and boys, while GGT and bilirubin were comparable across age groups in girls and increased slightly with age in boys. Children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups. Concentrations of ALT, and to a lesser degree GGT, increased with age in boys with overweight or obesity. Optimal ALT cut-points for diagnosing hepatic steatosis (liver fat content > 5%) was 24.5 U/L for girls (sensitivity: 55.6%, specificity: 84.0%), and 34.5 U/L for boys (sensitivity: 83.7%, specificity: 68.2%)., Conclusions: Pediatric normal values of liver enzymes vary with both age and sex. Overweight and obesity is associated with elevated biochemical markers of liver damage. These findings emphasize the need for prevention and treatment of overweight and obesity in children and adolescents. (J Clin Endocrinol Metab XX: 0-0, 2019)., (Published by Oxford University Press on behalf of the Endocrine Society 2019.)

Cardiac surgery with cardiopulmonary bypass (CPB) causes an acute lung ischemia-reperfusion injury, which can develop to pulmonary dysfunction postoperatively. This sub-study of the Pulmonary Protection Trial aimed to elucidate changes in arterial blood gas analyses, inflammatory protein interleukin-6, and metabolites of 90 chronic obstructive pulmonary disease patients following two lung protective regimens of pulmonary artery perfusion with either hypothermic histidine-tryptophan-ketoglutarate (HTK) solution or normothermic oxygenated blood during CPB, compared to the standard CPB with no pulmonary perfusion. Blood was collected at six time points before, during, and up to 20 h post-CPB. Blood gas analysis, enzyme-linked immunosorbent assay, and nuclear magnetic resonance spectroscopy were used, and multivariate and univariate statistical analyses were performed. All patients had decreased gas exchange, augmented inflammation, and metabolite alteration during and after CPB. While no difference was observed between patients receiving oxygenated blood and standard CPB, patients receiving HTK solution had an excess of metabolites involved in energy production and detoxification of reactive oxygen species. Also, patients receiving HTK suffered a transient isotonic hyponatremia that resolved within 20 h post-CPB. Additional studies are needed to further elucidate how to diminish lung ischemia-reperfusion injury during CPB, and thereby, reduce the risk of developing severe postoperative pulmonary dysfunction.