Does low birth weight affect the presence of cardiometabolic risk factors in overweight and obese children?

UNLABELLED: Recent findings suggest that low-birth-weight children with current obesity are more likely to have higher systolic blood pressure levels and impaired ß-cell function than those who are obese with normal birth weight. It seems possible, however, that concurrent low birth weight with excess weight gain can exacerbate other risk factors for cardiometabolic diseases. The purpose of this study is to investigate the influence of birth weight on the lipid/apolipoprotein profile, visfatin levels, and insulin parameters in overweight/obese children. A cross-sectional study of 68 overweight/obese children was conducted. Among these children, 28 were identified with low birth weight and 40 were of normal birth weight. Blood lipid profile, apolipoproteins, visfatin, glucose, and insulin were measured. Our results show that systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels, triglycerides (TG), very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), apolipoprotein B and E, insulin, apolipoprotein B/A1 ratio, and homeostasis model assessment insulin resistance (HOMA-IR) were significantly elevated in overweight/obese low-birth-weight (LBW) children. There was a significant association of the SBP levels with TG (P=0.027), LDLc (P=0.001), HOMA-IR (P<0.001), apolipoprotein B (P=0.001), and apolipoprotein E (P=0.039). CONCLUSION: Our findings suggest that LBW children with overweight or obesity have an additional risk factor for both atherogenic and insulinogenic profile.

Influence of birth weight on the renal development and kidney diseases in adulthood: experimental and clinical evidence.

Several clinical and experimental studies support the hypothesis that foetal programming is an important determinant of nephropathy, hypertension, coronary heart disease, and type 2 diabetes during adulthood. In this paper, the renal repercussions of foetal programming are emphasised, and the physiopathological mechanisms are discussed. The programming of renal diseases is detailed based on the findings of kidney development and functional parameters.

Association of ACE gene insertion/deletion polymorphism with birth weight, blood pressure levels, and ACE activity in healthy children.

BACKGROUND: The human angiotensin-converting enzyme (ACE) gene contains a polymorphism consisting of either an insertion (I) or a deletion (D) of a 287 bp Alu repetitive sequence in intron 16. The potential role of ACE polymorphism in the risk of developing hypertension or other cardiovascular disorders has not been determined in relation to birth weight (BW). METHODS: The ACE genotype and plasma ACE activity were determined in 167 children. Among these children, 60 were identified with low BW (LBW), and 107 were of normal BW (NBW). RESULTS: ACE activity levels were significantly elevated in LBW children compared with the NBW group (P < 0.001). There was a significant association of the ACE activity with systolic blood pressure (SBP) levels in our population (P < 0.001). Among the ACE genotypes, no significant differences were found with respect to BW (P = 0.136). However, our results revealed that LBW children had a higher D allele frequency than NBW children (P = 0.036). When analyzed by quartiles of SBP or ACE activity, we found a greater frequency of both the LBW children and those carrying the DD genotype in the highest quartiles of these parameters, whereas the NBW children tended to be in the lowest quartile (P < 0.001). Similar results were observed with the heterozygote ID children after categorization by quartiles of both SBP (P < 0.001) and ACE activity (P = 0.004). CONCLUSIONS: The ACE I/D polymorphism, especially the DD genotype, can be interpreted as a major factor in association between LBW and high BP levels.

Abnormalities in metalloproteinase pathways and IGF-I axis: a link between birth weight, hypertension, and vascular damage in childhood.

BACKGROUND: Although numerous studies suggest an inverse relationship between birth weight and cardiovascular disease, the mechanistic basis of this phenomenon is not fully understood. Here, we postulate that alterations in plasma concentration of matrix metalloproteinases (MMPs) and growth factors might show different associations between birth weight, blood pressure levels, and vascular function. METHODS: Concentrations of MMP-2 and its tissue inhibitor 2 (TIMP-2), MMP-9, and insulin-like growth factor-I (IGF-I) and its binding protein IGFBP-3 were measured in 64 children (34 boys, 30 girls). RESULTS: Small-for-gestational-age children exhibited elevated amounts of MMP-2, MMP-9, MMP-2/TIMP-2 ratio, MMP-9/TIMP-2 ratio, as well as lower concentration of IGF-I (P < 0.01), a known regulator of elastin synthesis. Similar findings were observed after adjustment for current age, gender, and race. The changes in the circulating levels of MMP-2, MMP-9, and IGF-I correlated significantly with birth weight, systolic blood pressure, and vascular function. Stepwise regression analysis demonstrated that MMP-2 was found to be an independent predictor of systolic blood pressure (R(2) = 0.08), whereas MMP-9 and birth weight were independent predictors of vascular dysfunction (R(2) = 0.38). CONCLUSIONS: It is possible that the association of fetal programming with elevated risk for vascular and metabolic disease in later life is, at least in part, mediated by perturbations in the MMP pathways.

Blood pressure levels in childhood: probing the relative importance of birth weight and current size.

Several studies have reported data supporting the idea that an impaired intrauterine environment that deprives the fetus of optimal nutrient delivery results in the predisposition of the fetus to experience cardiovascular and metabolic dysfunction in later life. However, contradictory data still exist. Our purpose was to investigate the effects of both birth weight and weight gain on the risk for high blood pressure levels in 6- to 10-year-old children. This cross-sectional study included 739 children divided into quartiles of birth weight. The mean values of both systolic and diastolic pressure were significantly different between quartiles of birth weight, with increasing blood pressure values as the birth weight decreased (P<0.001). Covariance analysis adjusting for gender, prematurity, and body mass index (BMI) showed that both systolic and diastolic pressure remained greater in the lowest than in the highest birth weight quartile. Separating those with low and normal birth weight demonstrated that the risk of childhood hypertension was significantly higher among children with low birth weight and current obesity (odds ratio [OR]: 5.0, confidence interval [CI]: 3.3 to 16.1; P=0.023). The inverse association between birth weight and blood pressure levels appears to be programmed during fetal life, while weight gain during childhood adds to this risk.

Stunting growth: association of the blood pressure levels and ACE activity in early childhood.

Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II and inactive bradykinin. Several studies carried out in our laboratory have consistently identified three isoforms of ACE, at 65, 90 and 190 kDa, with the 90-kDa isoform being a possible genetic marker of hypertension. Based on these observations and the fact that nutritional stunting can be associated with hypertension, we have investigated the expression and activity of ACE in stunted children and its association with blood pressure (BP) levels and nutritional state. Sixty children aged 2-7 years were selected for this study. A urine sample was collected from each child. Angiotensin converting enzyme activity was evaluated using two different substrates, and ACE expression was detected by Western blotting. Our results show that nutritional stunting is associated with high ACE activity in childhood and that adjustment by gender does not modify the strength of this association. A greater percentage of stunted children had increased BP levels, and this clinical parameter was inversely correlated with anthropometric indicators. A greater urinary protein expression of the three ACE isoforms was observed in the group of children with growth stunting. Our findings suggest that the reported high risk of hypertension in stunted adolescents and adults are, at least partly, associated with abnormalities in the renin-angiotensin system.

GFR estimated from cystatin C versus creatinine in children born small for gestational age.

BACKGROUND: Low birth weight caused by intrauterine growth restriction may be a risk factor for renal impairment in the adult life. STUDY DESIGN: A cross-sectional study. SETTING & PARTICIPANTS: 71 children aged 8 to 13 years living in the community of São Paulo, Brazil, were included in the study. Gestational age was within the normal range. PREDICTORS: Birth weight (range, 2,052 to 3,560 g) divided into quartiles: 2,500 g or less; 2,501 to 2,740 g; 2,741 to 3,000 g; and greater than 3,000 g. Birth weight ascertained by birth records in 43 and by recall in 28 participants. OUTCOMES & MEASUREMENTS: Cystatin C, creatinine, and glomerular filtration rate (GFR) estimated by equations using cystatin C (eGFR(cys)) or creatinine (eGFR(cr)). RESULTS: Overall, mean serum creatinine level was 0.8 +/- 0.01 (SE) mg/dL (range, 0.7 to 1.1 mg/dL); mean plasma cystatin C level was 0.9 +/- 0.02 mg/L (range, 0.5 to 1.6 mg/L), and eGFR(cr) and eGFR(cys) were 102.4 +/- 2.16 (range, 66 to 140) and 91.8 +/- 2.46 mL/min/1.73 m(2) (range, 49 to 139 mL/min/1.73 m(2)), respectively. No differences were found for serum creatinine or eGFR(cr) values among the birth-weight quartiles. There was a significant linear trend of increasing cystatin C levels (decreasing eGFR(cys)) in the lower birth-weight quartile groups (P = 0.002 and P = 0.02, respectively). Systolic blood pressure correlated with plasma cystatin C level (r = 0.31; P = 0.008) and eGFR(cys) (r = -0.26; P = 0.028). Covariance analysis adjusting for age, sex, body mass index for age compared with standards of the National Center for Health Statistics and expressed as a z score, and systolic blood pressure showed that cystatin C values remained greater in the lowest than highest birth-weight quartile (1.01 +/- 0.05 versus 0.83 +/- 0.05 mg/L; P = 0.02). LIMITATIONS: Ascertainment of birth weight by recall in some participants. Lack of measurement of microalbuminuria, absence of direct GFR measurement, and small sample size. CONCLUSIONS: Lower birth weight is associated with higher levels of cystatin C but not creatinine in 8-13 yr. old children born full-term.

Circulating renin-angiotensin system and catecholamines in childhood: is there a role for birthweight?

There have been only a few reports on the sympathoadrenal and renin-angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n=31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n=35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls (P=0.036). In addition, angiotensin II and ACE activity were higher in SGA boys (P=0.024 and P=0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin-angiotensin systems into later childhood.

Biomarkers of oxidative stress and antioxidant status in children born small for gestational age: evidence of lipid peroxidation.

Children born small for gestational age are known to be at increased risk for adult diseases such as hypertension, diabetes, and coronary heart disease. Oxidative stress is a common feature of these pathogenic conditions and can be the key link between size at birth and increased morbidity later in life. The purpose of this study was to analyze the parameters of lipoperoxidation and changes in antioxidant defense system as well as assess their relationship to birth weight. Concentrations of thiobarbituric-acid-reactive-substances and F2-isoprostanes, total antioxidant status, and the activity of both superoxide dismutase and glutathione peroxidase were measured in 65 children (33 boys, 32 girls; ages 8-13 y). Thiobarbituric-acid-reactive-substances and F2-isoprostane levels were significantly elevated in children born small for gestational age. Nevertheless, superoxide dismutase activity was significantly elevated in these children and the levels of both glutathione peroxidase activity and total antioxidant status were unchanged. Moreover, we found that systolic blood pressure was positively associated with thiobarbituric-acid-reactive-substances levels in race- and gender-adjusted models but not in a multivariable regression model. In conclusion, the current study revealed that there is evidence of oxidative stress in children born small for gestational age as supported by increased lipid peroxidation.

Homocysteine and nitric oxide are related to blood pressure and vascular function in small-for-gestational-age children.

Leptin, homocysteine (Hcy), and C-reactive protein are risk factors potentially useful in predicting future cardiac events. These plasma biomarkers may participate in the regulation of cardiovascular function through an NO-dependent mechanism. Our purpose was to investigate whether alterations in C-reactive protein, Hcy, leptin, and NO are present in small-for-gestational-age children and to determine whether the levels of these plasma biomarkers are associated with birth weight, vascular function, and blood pressure. Concentrations of leptin, Hcy, C-reactive protein, and NO were measured in 69 children (36 boys and 33 girls; ages 8 to 13 years). Leptin (means difference: 1.4 ng/mL; 95% CI: 0.4 to 2.4) and Hcy (means difference: 0.9 micromol/L; 95% CI: 0.3 to 1.5) levels were significantly elevated in children born small for gestational age compared with those with appropriate birth weight. Nevertheless, NO (means difference: 342.9 micromol; 95% CI: 124.2 to 561.6) concentration was significantly reduced in small birth weight children, and the levels of C-reactive protein remained unchanged. There was a significant association between the circulating levels of both NO and Hcy with vascular function, as well as with blood pressure levels, in our population. Because both Hcy and NO are associated with a risk of cardiovascular disease, it is possible that part of the association of low birth weight with elevated risk for vascular and metabolic disease in later life is mediated by perturbation in pathways for these biomarkers.

Long-term effects of intrauterine malnutrition on vascular function in female offspring: implications of oxidative stress.

Maternal malnutrition is known to impair fetal growth and predispose to the development of hypertension and type 2 diabetes. Recently, studies have demonstrated that intrauterine malnutrition is followed later in male offspring by oxidative stress characterized by increased superoxide generation due to activation of NADPH oxidase and reduced antioxidant defenses. However, few studies have investigated the mechanisms involved in endothelial dysfunction in female offspring. We evaluated the effects of the exogenous application of superoxide scavengers on the endothelium-dependent vasorelaxation in the mesenteric microvessels of female offspring. In addition, we examined indicative parameters of oxidative stress by measuring superoxide anion concentration and the activity of superoxide dismutase (SOD) as a marker of antioxidant defenses. Pregnant female Wistar rats were fed either a normal diet or 50% of this, throughout gestation. Intrauterine malnutrition induced hypertension and increased superoxide production without affecting SOD activity. Topical application of MnTMPyP (SOD mimetic) and apocynin (NADPH oxidase inhibitor) significantly improved the altered arteriolar responses to acetylcholine and bradykinin. In addition, incubation with apocynin reduced superoxide generation in these female offspring. The data suggest that after exposure to intrauterine malnutrition, female offspring present an increased superoxide production that is, at least in part, responsible for an endothelial dysfunction observed in these animals. These effects may be mediated via modulation of enzyme systems that generate superoxide.

Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats.

Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension and endothelial dysfunction in adulthood. We have evaluated the effect of the Renin Angiotensin System inhibition on the blood pressure and the mesenteric arteriolar reactivity of the intrauterine undernourished rats. Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. In this study only the male offspring was used. At 16 weeks of age, the rats were used for the study of blood pressure, microvascular reactivity studied in vivo-in situ to Angiotensin II (Ang II), Bradykinin (Bk) and Acetylcholine (Ach) before and after either losartan (10 mg/kg/15 days) or enalapril (15 mg/kg/21 days) treatment. We also evaluated the mesenteric and plasmatic Angiotensin Converting Enzyme (ACE), renal function, lipid plasmatic content, and insulin and glucose metabolism. Intrauterine undernutrition induced hypertension and increased response of mesenteric arterioles to Ang II and decreased vasodilation to Bk and Ach. The treatments with losartan or enalapril normalized the blood pressure levels and significantly improved the arteriolar responses to Bk, Ach and reduced the response to Ang II. No differences have been detected to ACE activity, renal function, lipid content and insulin and glucose metabolism. This study shows for the first time that Renin Angiotensin System inhibitors can normalize the cardiovascular alterations induced by intrauterine undernutrition.

Effects of low birth weight in 8- to 13-year-old children: implications in endothelial function and uric acid levels.

Low birth weight has been associated with an increased incidence of adult cardiovascular disease. Endothelial dysfunction and high levels of serum uric acid are associated with hypertension. In this study, we have determined whether uric acid is related to blood pressure and vascular function in children with low birth weight. We evaluated vascular function using high-resolution ultrasound, blood pressure, and uric acid levels in 78 children (35 girls, 43 boys, aged 8 to 13 years). Increasing levels of uric acid and systolic blood pressure were observed in children with low birth weight. Birth weight was inversely associated with both systolic blood pressure and uric acid; on the other hand, uric acid levels were directly correlated with systolic blood pressure in children of the entire cohort. Low birth weight was associated with reduced flow-mediated dilation (r=0.427, P<0.001). Because the children with low birth weight had elevated uric acid as well as higher systolic blood pressure levels, we evaluated the correlation between these variables. In the low birth weight group, multiple regression analysis revealed that uric acid (beta=-2.886; SE=1.393; P=0.040) had a graded inverse relationship with flow-mediated dilation, which was not affected in a model adjusting for race and gender. We conclude that children with a history of low birth weight show impaired endothelial function and increased blood pressure and uric acid levels. These findings may be early expressions of vascular compromise, contributing to susceptibility to disease in adult life.