Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (ß = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (ß = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (ß = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (ß = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (ß = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

OBJECTIVE: To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. DESIGN: Cross-sectional comparison of serum biomarkers. SETTING: University Medical Center Utrecht. PATIENTS: Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30). MAIN OUTCOME MEASURE(S): Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). RESULTS: The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. CONCLUSION: In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.

Relation Between Circulating Inflammatory Chemokines and Vascular Characteristics in Healthy, Young Children.

BACKGROUND: Atherosclerosis begins in childhood with the occurrence of inflammatory vascular wall alterations that are detectable with B-mode ultrasound. Chemokines appear to be involved in the development of these alterations given that they occur early in the atherosclerotic pathway as mediators of vascular inflammation. However, this has not extensively been investigated. Therefore, we studied in healthy young children whether chemokines monocyte chemotactic protein 1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and vascular and intercellular adhesion molecules (VCAM and ICAM) related to vascular characteristics of the carotid artery. METHODS AND RESULTS: We obtained demography, anthropometry, and overnight fasting plasma of 139 eight-year-old children of the Wheezing Illnesses Study Leidsche Rijn birth cohort. Carotid intima-media thickness (CIMT), distensibility, and Young's Elastic Modulus (YEM) of the common carotid artery were measured sonographically. Chemokine plasma levels were assessed using a multiplex assay. We studied the relation between the chemokines and vascular characteristics using multivariable linear regression analyses with adjustments for sex, systolic blood pressure, homeostasis model assessment of insulin resistance, triglycerides, low-density lipoprotein- and high-density lipoprotein-cholesterol. Of the studied chemokines, RANTES related to common carotid distensibility and YEM. One standard deviation increase in RANTES level related to a 5.45-MPA(-1) (95% confidence interval [CI], -9.43, -1.39; P=0.01) decrease in distensibility and to a 5.55-kPa increase in YEM (95% CI, 0.40, 10.85; P=0.03). RANTES did not relate to CIMT. MCP-1, VCAM, and ICAM did not relate to any of the studied vascular characteristics. CONCLUSION: RANTES appears to be involved in the development of preatherosclerotic inflammatory vascular alterations already in healthy, young children. This may provide further insight into the early-life origins of atherosclerosis.

Allergies are associated with arterial changes in young children.

BACKGROUND: Inflammation is important in atherosclerosis development. Whether common causes of inflammation, such as allergies and infections, already exert this influence in early childhood is unknown. The objective of this study was to investigate the association between both allergies and infections with children's vasculature. DESIGN: This was a longitudinal study in a general population cohort. METHODS: In 390 five-year-olds of the WHISTLER (Wheezing-Illnesses-Study-LEidsche-Rijn) birth cohort, carotid intima-media thickness (CIMT) and arterial stiffness were obtained ultrasonographically. Physician-diagnosed allergies and infections and recent prescriptions of systemic antihistamines and antibiotics were obtained, as well as parental history of allergies. General linear regression was performed with vascular characteristics as dependent variables and measures of inflammation as independent variables. RESULTS: Having both a positive parental history of allergy and an allergy diagnosis showed 15.0 µm (95% confidence interval (CI): 2.3-27.8, p = 0.02) larger CIMT than not having such history and diagnosis. Having a positive parental history of allergy only showed 11.9 µm (0.87-23.0, p = 0.04) larger CIMT. Recent use of antihistamines and antibiotics showed 18.8 µm (1.6-35.9, p = 0.03) and 16.1 µm (4.5-27.7, p = 0.01) larger CIMT, respectively. Childhood infections were not clearly related to vascular parameters. Neither allergy nor infections were associated with arterial stiffness. CONCLUSION: An allergic predisposition is already associated with thicker arterial walls in early childhood.

Effect of physical activity on vascular characteristics in young children.

BACKGROUND: Physical activity has long been proposed as an important modifiable cardiovascular risk factor in adults. We assessed whether physical activity already has an effect on childhood vasculature. METHODS: In the Wheezing-Illnesses-Study-in-Leidsche-Rijn birth cohort, we performed vascular ultrasound to measure carotid intima-media thickness (cIMT) and functional properties (distensibility, elastic modulus) at 5 and 8 years of age. Child typical physical activities were inquired using a questionnaire completed by parents. Linear regression was used with physical activity level, expressed as a standardized value of time-weighted metabolic equivalent (MET) as the independent variable and vascular properties as dependent variables with further confounder adjustment and evaluation for possible body mass index and sex effect modifications. RESULTS: In 595 5-year-old children and in 237 of those who had reached the age of 8 years, we did not find statistically significant associations between total time-weighted MET and each vascular parameter, neither in pooled nor stratified analysis. However, sport activities were associated with thinner cIMT (-3.20 µm/SD, 95% CI -6.34, -0.22, p = 0.04) at 5 years of age; a similar pattern was seen for organized sport. This effect was strongest in children in the highest body mass index tertile (-5.38 µm/SD, 95% CI -10.54, -0.19, p = 0.04). At the age of 8 years, higher sport level tended to be associated with higher vascular distensibility (2.64 × 10(3) kPa/SD, 95% CI -0.18, 5.45, p = 0.07) although this was not statistically significant. CONCLUSIONS: Sport activity may have beneficial effects on arteries of young children, particularly those with higher relative body weight.

Life-course of cardio-respiratory associations.

BACKGROUND: Several studies have shown that raised cardiovascular risk factors are associated with an impaired lung function in adulthood. Whether this association also exists in the young is unknown. Our aim was to study the relation between blood pressure and lung function from neonatal to elderly age. STUDY DESIGN: This was a cross-sectional study in a general population cohort. METHODS: Within the Utrecht Health Project (UHP) 6673 adults (aged 18-91 years) had spirometry and blood pressure measurements taken. In the WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) study, a satellite birth cohort of the UHP, blood pressure and respiratory mechanics were measured using the single occlusion technique in 755 newborns and spirometry in 382 5-year-old participants. Linear regression analyses were performed with lung function as an independent variable and blood pressure as a dependent variable in different age groups. The analyses were adjusted for age, sex, weight and height. RESULTS: In infancy a more favorable lung function (higher compliance and lower resistance) was associated with higher blood pressure. In 5-year-old children and young adults higher forced expiratory volume in 1 second (FEV1) was associated with higher systolic blood pressure (p-values < 0.05). At the age of 5 the adjusted regression coefficient for systolic blood pressure was 4.8 mmHg/L (95% confidence interval (95% CI) -0.3-9.98). The association decreased with increasing age and reversed in the age groups above 40 years to -7.3 mmHg/L (95% CI -15.5-0.9) in those aged over 70 years of age. The association with pulse pressure showed a similar pattern. CONCLUSIONS: A positive association between the mechanical properties of the respiratory system and blood pressure in childhood and young adulthood reverses in later adulthood.

Extracellular vesicle protein CD14 relates to common carotid intima-media thickness in eight-year-old children.

BACKGROUND: Atherosclerosis is a process that begins in childhood, develops over decades and underlies the majority of cardiovascular events in adulthood. Previously, we demonstrated in adults with cardiovascular disease that levels of extracellular vesicle (EV) proteins CD14, Serpin F2 and cystatin C predict vascular outcome. Here, we study for the first time whether these EV proteins are related to vascular characteristics in healthy, young children. METHODS AND RESULTS: In 141 eight-year old children of the Wheezing-Illnesses-Studie-LEidsche-Rijn birth cohort, anthropometrics and blood pressure were measured. In addition, common carotid intima-media thickness, carotid distensibility and carotid Young's elastic modulus were obtained non-invasively using ultrasound imaging. A fasting lipid spectrum was obtained and EVs were isolated from plasma. Levels of EV proteins CD14, Serpin F2 and cystatin C were measured using a multiplex assay. In a multivariable linear regression model we assessed the relation between these EV proteins and the selected vascular characteristics. Of the studied EV proteins, CD14 levels were positively related to common carotid intima-media thickness (log transformed, beta = 7.31 ln(mm)/(ng/mg) (1.24, 13.38), p = 0.02). EV proteins Serpin F2 and cystatin C were not related to common carotid intima-media thickness. In addition, we found no relation between all three EV proteins and carotid distensibility or carotid Young's elastic modulus. CONCLUSION: In healthy eight-year old children, extracellular vesicle protein CD14 levels seem positively related to common carotid intima-media thickness. This would point towards inflammatory vascular alterations inflicted by extracellular vesicle protein CD14 already in early life and warrants further investigation.

Excess early postnatal weight gain leads to thicker and stiffer arteries in young children.

BACKGROUND: Although early life growth pattern is associated with cardiovascular disease later in life, it is unknown whether vascular changes associated with excess early weight gain already occur in early childhood. METHODS: In the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort, weight and height from birth to 3 months of age were used to calculate Z-scores of individual weight and length gain rates. In the first 333 children who turned 5 years old, intima-media thickness, distensibility, and elastic modulus of the carotid artery were measured ultrasonographically. The association between weight gain rate for length gain rate (WLG), as a measure of excess weight gain, and vascular characteristics was assessed by generalized linear modeling. Interaction between birth size and WLG was tested. RESULTS: Per 1 SD increase in WLG, carotid intima-media thickness was 5.1 µm (95% confidence interval, 1.0-9.2; P value = .01) higher (adjusted for age, gender, current height, and observer). The thinner the children were at birth, the stiffer the arteries were with increasing WLG (interaction between birth size and WLG-distensibility: P = .04; elastic modulus: P = .03). CONCLUSION: Excess early postnatal weight gain leads to vascular changes already in early childhood, characterized by thicker arterial walls. In children who are relatively thin at birth, excess early postnatal weight gain also leads to stiffer arteries. This supports the view that cardiovascular disease risk is associated with growth pattern early in life.

Parental blood pressure is related to vascular properties of their 5-year-old offspring.

BACKGROUND: Adolescent offspring of hypertensive parents have increased carotid intima media thickness (CIMT) and arterial stiffness compared with offspring of normotensives. We assessed whether systolic blood pressure (SBP) of both parents is associated with the vasculature of their offspring as early as in childhood. METHODS: In the first 306 5-year-old children of the Wheezing-Illnesses-Study-Leidsche-Rijn birth cohort, CIMT, distensibility, and elastic modulus (EM) were obtained ultrasonographically. In 204 of 306 (67%) children, complete data on both maternal and paternal SBP were obtained from the linked database of the Utrecht Health Project. RESULTS: CIMT of the children was 0.58 µm (95% confidence interval (CI): 0.14, 1.0) greater with every 1-mm Hg higher maternal SBP. Maternal SBP and children's distensibility and EM were more strongly associated, negative and positive respectively, with increasing paternal SBP and vice versa (P value-for-interaction: 0.003 and 0.001, respectively). CIMT of children of whom both parents were in the highest SBP tertile was 17.9 µm (95% CI: 4.0, 31.9) greater compared with the CIMT of children of whom neither one of the parents had a SBP in the highest tertile. For EM and distensibility, these estimates were 20.1 kPa (95% CI: 1.1, 39.2) and -11.6 1/Mpa (95%-CI: -22.9, -0.31), respectively. CONCLUSIONS: Higher maternal SBP is related to thicker arterial walls in their 5-year-old offspring. If both parents have higher SBP, the arterial wall of their offspring is thicker and stiffer.

Excess early postnatal weight gain leads to increased abdominal fat in young children.

Background. Increased childhood weight gain has been associated with later adiposity. Whether excess early postnatal weight gain plays a role in childhood abdominal fat is unknown. Design. In the ongoing Wheezing Illnesses Study Leidsche Rijn (WHISTLER), birth cohort weight and length from birth to age 3 months were obtained. In the first 316 five-year-olds, intra-abdominal and subcutaneous fat were measured ultrasonographically. Individual weight and length gain rates were assessed in each child. Internal Z-scores of weight for length gain (WLG) were calculated. Multiple imputation was used to deal with missing covariates. Results. Per-1-unit increase in Z-score WLG from birth to 3 months, BMI, waist circumference, and subcutaneous fat were significantly higher; 0.51 kg/m(2), 0.84 cm, and 0.50 mm, respectively. After multiple imputation, a trend towards significance was observed for intra-abdominal fat as well (0.51 mm/SD). In the associations with 5-year adiposity, no interaction between postnatal Z-score WLG and birth size was found. Conclusion. Excess early postnatal weight gain is associated with increased general and central adiposity, characterized by more subcutaneous and likely more intra-abdominal fat at 5 years of age.

Body fat distribution and early arterial changes in healthy 5-year-old children.

BACKGROUND: It is unknown at what age overweight starts to takes its toll on the vasculature. We studied the relation between body size measures and vascular characteristics in healthy 5-year-old children. METHODS: In 306 5-year-old children from an on-going birth cohort, body size characteristics were measured, including sonographic measurement of abdominal fat. Ultrasonographic measurements of the carotid artery were performed to obtain intima-media thickness (CIMT), arterial wall distensibility, and elastic modulus (EM). RESULTS: Increased body-weight was related to thicker CIMT (linear regression coefficient 2.25 µm/kg; P = 0.003), increased EM (2.73 kPa/kg; P = 0.01), and lower distensibility (-1.23 MPa(-1)/kg; P = 0.03). Similar relations were found for increased BMI with CIMT and EM. Increased intra-abdominal fat was related to thicker CIMT (9.19 µm/cm; P = 0.02), and increased waist circumference with thicker CIMT (2.17 µm/cm; P = 0.02), lower distensibility (-1.70 MPa(-1)/cm; P = 0.01), and higher EM (2.77 kPa/cm; P = 0.02), independent of BMI. CONCLUSION: For the first time it is demonstrated that increased general body mass and particularly waist circumference and intra-abdominal fat are related to thicker and stiffer arteries already early in life.

The association between breastfeeding and the cardiovascular system in early childhood.

BACKGROUND: Breastfeeding is suggested to have beneficial effects on children's health and future health status. However, its cardiovascular effects in childhood and possibly later in life remain largely unclear. OBJECTIVE: The aim of the present study was to determine the cardiovascular effects of exclusive breastfeeding in early childhood. DESIGN: We used the ongoing WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) birth cohort to obtain data on infant feeding. In the first 306 children who were 5 y of age, ultrasonographic measurements of the carotid artery were performed to obtain carotid intima-media thickness (CIMT), distensibility, and elastic modulus. RESULTS: At 5 y of age, children who had been exclusively breastfed in infancy for 3 to 6 mo had a CIMT that was 21.1 µm greater than that of exclusively formula-fed children (95% CI: 5.0, 37.2 µm; P = 0.01, adjusted for confounders). CIMT was not significantly different between children exclusively breastfed for either <3 or >6 mo and formula-fed children. In addition, no significant differences in carotid stiffness were observed between groups. CONCLUSIONS: The duration of exclusive breastfeeding in infancy is related to properties of the carotid arterial wall at the age of 5 y, as shown by the greater CIMT in children who were exclusively breastfed for 3 to 6 mo. This relation was independent of early growth in infancy and current cardiovascular disease risk factors. The choice of infant feeding appears to have an effect on the vascular system already in early childhood.