Puberty and Microvascular Function in Healthy Children and Adolescents

Natural variability of lung function in young healthy school children.

This systematic review synthesized current literature regarding the effect of physical activity (PA) interventions on brain structure (BS) and brain function (BF) in healthy children. This review followed the Preferred Reporting Items for Systematic Reviews protocols and used the Rayyan web for data extraction. Eleven experimental studies were included. Specifically, six studies conducted chronic PA interventions, and the others applied acute PA interventions. Evidence from five articles (45.45%) confirmed that PA interventions had beneficial effects on brain structure and function in healthy children, including enhancing brain activation and microstructural plasticity. These articles shared a study protocol and were conducted in school settings, indicating homogeneity. Due to the technical complexity and limitations involved, there are few studies on brain health and development. Future research is necessary to validate and evaluate the effectiveness of PA interventions on brain structure and function in healthy children.

Recent epidemiological evidences indicates a complex association of hypertension with vascular endothelial dysfunction which causes the development and progression of atherosclerosis leading to adverse cardiovascular and cerebrovascular events due to reduction in nitric oxide (NO) bioavailability. The aim of the study was to investigate the value on reactive hyperemia peripheral arterial tonometry (RH-PAT) as a noninvasive tool to assess and compare endothelial function in between hypertensive and normotensives. Although they do not measure vascular function in the coronary circulation directly, they have been shown to correlate reasonably with its more invasive counterparts. A total of 73 hypertensive patients and 48 normotensive patients were consecutively recruited from Cardiology outpatient department of first affiliated hospital of Fujian medical university. Peripheral endothelial function was measured by using EndoPAT device to assess reactive hyperemia induced vasodilation and expressed by the reactive hyperemia index (RHI) with age, sex, BMI, height with the control subjects and further the relationship between RHI and clinical characteristics laboratory cardiovascular risk factors were also investigated. Statistical analysis were performed using SPSS software version 19.0. The normality of the distribution of variables were performed by the Kolmogorov-Smirnov test and homogeneity test of variance. Continuous variables were expressed as mean ± SD and categorical variables were expressed as percentages. Comparison between two normal groups were made by t-test, for abnormal distributed variables Mann-Whitney U test was used and χ2 test was performed for comparison of categorical variables. Pearson’s correlation analysis was used to assess associations between measured parameters and a p-value < 0.05 was considered to be statistically significant. RHI was significantly lower in hypertensive subjects compared to normotensive subjects (1.69 ± 0.46 vs 2.27 ± 0.60, p < 0.001) and when both groups were divided into different subgroups according to (sex, age < or ≥ 55, smoking, high cholesterol, physical activity, BMI, alcohol habit), significantly low RHI was noted in the hypertensive subgroups, p < 0.05. In the both groups there was no significant difference in normal cholesterol category where as in hypertensive group, subjects with regular physical activity had significantly high RHI as compared to those with no physical activity at all. In a univariate analysis age (r = -0.482, P = 0.001), Systolic BP (r = -0.312, P = 0.001), GFR (r = 0.196, P = 0.031), physical activity (r = 0.536, P = 0.001) were found to significantly correlate with RHI. In a multivariate analysis, only age (β = 0.004, P = 0.001) and SBP (β = 0.003, P = 0.010) significantly and independently correlated with RHI. RHI was significantly attenuated in hypertensive subjects and showed significant correlation between age, SBP, GFR, and physical activity indicating endothelial dysfunction, suggesting RH-PAT may be used as a non-invasive test to identify hypertensive patients with an early endothelial dysfunction.

Although an association of serum uric acid levels with endothelial function has been shown in various clinical settings, the optimal treatment target that would benefit vascular endothelial function has not been established. We, therefore, conducted a post hoc analysis of the Excited-UA study to identify an optimal target. Patients (N = 133) with chronic heart failure and comorbid hyperuricemia who enrolled in the Excited-UA study were divided into three tertiles based on their serum uric acid level 24 weeks after initiating xanthine oxidase inhibitor treatment with topiroxostat or allopurinol (i.e., groups with low, moderate, and high uric acid levels). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) values measured by reactive hyperemia peripheral arterial tonometry (RH-PAT) were compared among groups. The change from baseline in the FMD value 24 weeks after treatment was comparable among the three groups. In contrast, the change from baseline in the RHI was significantly different among the three groups (-0.153 ± 0.073, 0.141 ± 0.081 and -0.103 ± 0.104 in the low, moderate, and high uric acid level groups, respectively, P = 0.032). After adjustment for age, body mass index, and concomitant use of diuretics, which differed among the three groups, the change in the RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group (P = 0.057) and was significantly higher than that in the low uric acid level group (P = 0.020). These results indicate that targeting excessively low uric acid levels by treatment with xanthine oxidase inhibitors might be less beneficial for improving microvascular endothelial function in patients with chronic heart failure. Comparisons of the changes from baseline in vascular endothelial function parameters at 24 weeks among the 3 groups of low, moderae and high uric acid levels achieved with xanthine oxidase inhibitors. After adjustment for confounding factors, such as age, body mass index and concomitant diuretic use, which showed differences among the 3 groups, the change in RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group and was significantly higher than that in the low uric acid level group.

Ultrasound bone measurement in children and adolescents: Correlation with nutrition, puberty, anthropometry, and physical activity

Childhood obesity is increasingly recognized as a trigger for early cardiovascular risk, partly mediated by subclinical inflammation and endothelial dysfunction. This study aimed to evaluate the expression of pro-inflammatory cytokines (TNF-α, IL-17A, and IL-2) in whole blood and investigate their associations with anthropometric measures, blood pressure, microvascular endothelial function, and circulating apoptotic endothelial microparticles (EMPs) in children with healthy weight versus those with overweight/obesity. A cross-sectional study was conducted with 113 children aged 6-11 years, categorized as children with healthy weight (n = 82) or children with overweight/obesity (n = 31) based on BMI-for-age criteria. Endothelial function was assessed using peripheral arterial tonometry by measurement of reactive hyperemia index (RHI) and circulating apoptotic EMPs were measured by flow cytometry. Whole blood mRNA levels of inflammatory cytokines were quantified using qRT-PCR. Children with overweight/obesity exhibited significantly lower RHI values, indicating early endothelial dysfunction. RHI negatively correlated with BMI (r = -0.485; P < 0.001), waist circumference (r = -0.466; P < 0.001), SBP (r = -0.317, P = 0.001), DBP (r = -0.246; P = 0.009), and LDL-C levels (r = -0.191; P = 0.043). Circulating levels of apoptotic EMPs were elevated in these children and positively associated with adiposity and blood pressure, while inversely correlated with RHI (r = -0.496; P < 0.001). TNF-α expression was significantly upregulated in the overweight/obesity group and correlated positively with BMI (r = 0.468; P = 0.001), waist circumference (r = 0.492; P < 0.001), SBP (r = 0.294; P = 0.040), apoptotic EMPs (r = 0.326; P = 0.022), and negatively with RHI (r = -0.543; P < 0.001). No significant differences were observed for IL-17A or IL-2 expression. The linear regression analysis indicated that high circulating levels of both apoptotic EMPs and TNF-α mRNA were recognized as predictors factors of lower RHI value in the study population. TNF-α gene expression in whole blood and elevated levels of apoptotic endothelial microparticles are closely associated with early endothelial microvascular dysfunction in pediatric obesity. The observed associations underscore the role of inflammation-driven endothelial dysfunction in the pathophysiology of obesity-related cardiovascular risk.

To examine associations of maternal gestational diabetes mellitus (GDM) with offspring cardiovascular biomarkers from late childhood through adolescence. We used mixed effects linear regression models to examine associations of maternal GDM (n = 92 cases of 597) with average offspring levels of serum lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides) and systolic blood pressure (SBP) across two research visits spanning approximately 10.6 and 16.9 years of age. In sex-stratified analysis, we evaluated the impact of adjustment for sociodemographic characteristics, pubertal status, physical activity and total energy intake, maternal body mass index (BMI), GDM treatment, and child's BMI. After adjusting for child's age, pubertal status, race/ethnicity, and maternal education and smoking, GDM exposure was associated with higher total (0.38 [95% CI, 0.16-0.61] mmol/L) and LDL cholesterol (0.34 [95% CI, 0.14-0.53] mmol/L) in girls. These estimates were robust to adjustment for lifestyle characteristics and maternal BMI but were attenuated after accounting for GDM treatment with no appreciable change following further adjustment for current BMI. In boys, maternal GDM corresponded with 4.50 (1.90-7.10) mmHg higher SBP. This association persisted after accounting for sociodemographic/lifestyle characteristics, maternal BMI, and GDM treatment but was attenuated after adjusting for current BMI. Maternal GDM is related to offspring lipid profile and SBP in a sex-specific manner.

Objective: To investigate the mechanisms of wall shear stress (WSS) responsible for the effects of high-intensity interval exercise (HIIE) on vascular endothelial function in young obese males. Methods: A within-subject study design was used. We examined the response of the reactive hyperemia index (RHI) to acute HIIE in young obese males (n = 20, age = 20.38 ± 1.40 years, body mass index [BMI] = 31.22 ± 3.57, body fat percentage [BF (%)] = 31.76 ± 3.57). WSS was manipulated using 100, 80, or 60 mmHg cuff inflation during the HIIE to determine the proper inflation capable of maintaining WSS near baseline levels. One-way repeated measures analysis of variance and LSD post hoc tests were performed to compare changes in WSS and vascular endothelial function at baseline HIIE and following HIIE using different cuff inflations. Results: There were no significant differences in RHI and WSS between the three cuff inflation values (p > 0.05). WSS was significantly higher in obese male individuals after HIIE and HIIE with 100 mmHg cuff inflation (p = 0.018, p = 0.005) than that at baseline, with no significant differences observed comparing HIIE and HIIE with 100 mmHg inflation (p = 0.23). The RHI after HIIE was significantly higher (p = 0.012) than that at baseline, while no significant differences were detected after HIIE at 100 mmHg (p = 0.91). The RHI was significantly lower after HIIE with 100 mmHg than that after HIIE (p = 0.007). WSS (p = 0.004) and RHI (p = 0.017) were significantly higher after HIIE than that at baseline, while no significant differences were observed after HIIE with either 80 or 60 mmHg cuff inflation (baseline vs. HIIE + 80 mmHg: WSS: p = 0.33, RHI: p = 0.38; baseline vs. HIIE + 60 mmHg: WSS: p = 0.58, RHI: p = 0.45). WSS was similar to HIIE, after HIIE with either 80 or 60 mmHg inflation (p = 0.36, p = 0.40). However, RHI was significantly higher for HIIE than for HIIE with both 80 and 60 mmHg inflation (p = 0.011, p = 0.006). Conclusion: HIIE could significantly improve WSS and vascular endothelial function. HIIE intervention with 60 or 80 mmHg inflation might enhance WSS near the baseline level. HIIE-induced acute changes in WSS may provide the primary physiological stimulus for vascular endothelial adaptation to HIIE in young obese males.

Low testosterone in men predicts impaired arterial elasticity and microvascular function

Rationale: Endothelial dysfunction plays a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH). However, its assessment remains challenging, and available data is limited. Current PAH therapies target signaling pathways between endothelial cells and smooth muscle cells. Changes in peripheral microvascular endothelial function (PmvEF) might conform a surrogate marker of the impact of PAH therapies on pulmonary artery endothelial function. The study was aimed to evaluate PmvEF in patients with PAH at diagnosis and assess the effect of treatment. Methods: 35 patients (30 females, 59.7±15.6 years) with suspected PAH were evaluated at diagnosis. Right heart catheterization (RHC) confirmed PAH in 14 patients and ruled it out in 21 (control group). PmvEF was assessed by measuring reactive hyperemia peripheral arterial tonometry (PAT) after RHC, before starting PAH treatment. The percent change in reactive hyperemia index (RHI) and its logarithmic transformation (LnRHI) were used as markers of PmvEF. A second assessment of PmvEF was performed 3-6 months after initiating PAH therapy in 9 patients (4 monotherapy, 5 combined therapy). Results: Patients with PAH and controls had similar clinical characteristics, comorbidities and risk factors for PAH (Table 1). Likewise, PmvEF assessed by the RHI and the LnRHI was similar in both groups. Follow-up assessment in 9 patients with PAH after starting PAH therapy, showed a numerical increase in RHI and LnRHI (Table 1). Conclusions: These preliminary results indicate that at diagnosis, patients with PAH exhibit similar PmvEF than patients with a comparable clinical background without PH. PAH therapies improved PmvEF in a subset of patients. Further studies are underway to confirm these findings.

Bipolar disorder and related mood states are not associated with endothelial function of small arteries in adults without heart disease.

Endothelial function (EF) reflects the balance between vasodilatory and vasoconstrictive factors produced by (or acting on) the innermost lining of blood vessels. Endothelial dysfunction, an imbalance between these factors that favors vasoconstriction, has been associated with increased risk for cardiovascular disease. However, the influence of race/ethnicity and glycemic status on association between EF and cardiovascular risk factors remain to be clarified. We assessed EF in relation to glycemia and cardiometabolic profile in African-American (AA) and European-American (EA) offspring of parents with type 2 diabetes (T2D), who are participants in the prospective pathobiology and reversibility of prediabetes in a biracial cohort (PROP-ABC) study. Assessments at enrollment included a 75 g oral glucose tolerance test (OGTT), blood pressure, anthropometry, body composition (DEXA), and lipid profile. Other assessments were insulin sensitivity and resting energy expenditure. EF was measured using flow-mediated vasodilation (EndoPAT 2000) and expressed as reactive hyperemia index (RHI). We studied 190 subjects (100 AA, 90 C), mean age (±SD) 53.1 ± 9.1 years, and body mass index 30.6 ± 6.8 kg/m2. Based on OGTT data, 96 subjects (52 AA, 44 EA) had prediabetes and 94 subjects were normoglycemic (48 AA and 46 EA). The RHI was lower in AA than EA (2.17 ± 0.55 vs. 2.36 ± 0.72, P = 0.05) and in prediabetic than normoglycemic subjects (2.14 ± 0.62 vs. 2.38 ± 0.65, P = 0.013). Using RHI ≤ 1.68 as diagnostic cut-off, 19% of participants with prediabetes and 10% of normoglycemic participants had endothelial dysfunction (P = 0.04). In univariate models, RHI was positively associated with age and HDL cholesterol levels, and inversely associated with adiposity, diastolic blood pressure, and 2hr plasma glucose. The association between RHI and adiposity was stronger in men than women. The association between RHI and age, glucose and HDL cholesterol displayed marked ethnic disparities. In our biracial cohort comprising offspring of parents with T2D, prediabetes increased the risk of endothelial dysfunction. However, the association between EF and cardiometabolic risk factors was significantly modified by ethnicity and gender. Our findings support current understanding of endothelial dysfunction as an early sensitive indicator of cardiometabolic risk.

Introduction:Psychosocial stressors deriving from socioeconomic disadvantages in adolescents can result in higher metabolic syndrome (MetS) risk. We aimed to examine whether socioeconomic disadvantages were associated with MetS independent of lifestyle and whether there was a dose response relationship between the number of cumulated socioeconomic disadvantages and the risk of MetS.Materials and Methods:The present study included 1,037 European adolescents (aged 12.5–17.5) of the 3,528 total HELENA participants. Sociodemographic variables and lifestyle were assessed through self-reported questionnaires. Disadvantaged groups included adolescents with low educated parents, low family affluence, migrant origin, unemployed parents, and from non-traditional families. MetS score was calculated as the sum of sex- and age-specific z-scores of waist circumference, HOMA-IR index, mean of z-scores of diastolic and systolic blood pressure and mean of z-score of HDL-C multiplied by -1 and z-score of TG. A higher score indicates poor metabolic health. Linear mixed-effects models were used to study the association between social disadvantages and MetS risk score. Models were adjusted for sex, age, pubertal status (Tanner stage) and lifestyle (diet quality, physical activity, alcohol consumption and smoking status).Results:Adolescents with low educated mothers showed a higher MetS score (0.54 [0.09–0.98]; β [99% confidence interval]) compared to high-educated mothers. Adolescents who accumulated more than three disadvantages (0.69 [0.08–1.31]) or with missing information on disadvantages (0.72 [0.04–1.40]) had a higher MetS risk compared to non-socioeconomically disadvantaged groups. Stronger associations between socioeconomic disadvantages and MetS were found in male in comparison with female adolescents.Discussion:Out of the studied socioeconomic disadvantages, maternal education is the most important determinant of adolescent's MetS risk independently of sex, age, Tanner stage, smoking status, alcohol consumption, diet quality and physical activity. Social vulnerabilities (migrant background, unemployment status and belonging to a non-traditional family) were not associated with a higher MetS risk in European adolescents. However, we found a dose-response relationship between the number of factors related to social disadvantage and adolescents’ MetS risk with adolescents accumulating three or more socioeconomic disadvantages showing the highest risk. Stronger associations between socioeconomic disadvantages and MetS were found in male compared to female adolescents. Policy makers should focus on low educated families to tackle health disparities.

Polymorphism of the bradykinin type 2 receptor gene modulates blood pressure profile and microvascular function in prepubescent children

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00223600.