Propeptide Of C-type Natriuretic Peptide Research Articles

Discrepant Inferences When Modeling Associations Between Time-Varying Exposures and Linear Growth Trajectories in Infancy Using Length-For-Age Z Scores Versus Raw Length

Abstract Objectives To compare inferences from longitudinal models of the relationships between biomarkers of interest and linear growth outcomes in infancy using length-for-age z-scores (LAZ) based on age- and sex-specific growth standards, or raw length. Methods This was a secondary analysis of data from a study of the association between bone-related biomarkers and infant linear growth trajectories up to 1 year of life in a subset of infants (n = 820) enrolled in the Maternal Vitamin D for Infant Growth trial. The linear growth outcome (LAZ or raw length) was modelled as a function of the interaction between each biomarker and age using linear mixed effect models with restricted cubic splines. Models were specified to obtain the best fit and reconcile discrepancies in results from LAZ and length models. Inferences from marginal effects at birth, 3 months, 6 months, and 12 months were compared, for a total 4 effect estimates from each of 10 pairs of LAZ and length models, resulting in 40 pairs of estimates. The following biomarkers were included: fibroblast growth factor 21 (FGF21), fibroblast growth factor 23 (FGF23), N-terminal propeptide of C-type natriuretic peptide (NT-proCNP), osteocalcin, osteoprotegerin, receptor activator of nuclear activator kappa-b ligand (RANKL), 25-hydroxyvitamin D (25OHD), C-reactive protein (CRP), Interleukin 6 (IL6), and insulin-like growth factor-1 (IGF1). Biomarkers were time-varying, measured in cord blood and at 3 and 6 months of age. Results The best fitting model for LAZ had 3 knots with random slopes, and the best fitting model for raw length had 5 knots, random slopes, and an exponential residual covariance structure. Comparisons of the pairs of marginal estimates from the LAZ vs length models resulted in discrepant inferences for 25% of effect estimates (10/40). Results were consistently concordant only for FGF23, 25OHD, CRP, and IL6. Conclusions Length and LAZ represent the same biological construct but their use in longitudinal modelling may lead to different inferences about associations between time-varying exposures and infant growth, possibly due to residual confounding by age. These findings raise concerns about the reliability of studies of determinants or markers of infant linear growth based on longitudinal modelling of growth trajectories. Funding Sources Bill and Melinda Gates Foundation.

Association of Bone Metabolism Biomarkers with Infant Linear Growth in a Birth Cohort from Dhaka, Bangladesh (P10-012-19)

ObjectivesTo estimate the associations of venous cord, infant 3-month, and 6-month bone-related biomarker concentrations (amino-terminal propeptide of C-type natriuretic peptide [NT-proCNP], fibroblast-like growth factor 21 [FGF21], receptor activator of nuclear activator kappa-b ligand [RANKL], osteoprotegerin [OPG], 25-hydroxyvitamin D [25OHD], FGF23, osteocalcin [OC], and insulin-like growth factor 1 [IGF-I]) with infant length-for-age z-score (LAZ) trajectories from 0 to 12 months of age, in Dhaka, Bangladesh. MethodsThis was a sub-study of the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh. NT-proCNP, FGF21, FGF23, and IGF-I were measured by ELISA, 25OHD by HPLC-tandem mass spectrometry, and OC, OPG, and RANKL by Milliplex magnetic panels. The primary outcome was LAZ from birth to 12 months of age. Among eligible infants (n = 569), associations between each biomarker and LAZ were estimated by linear mixed-effects models with restricted cubic splines. Significant biomarker-age interaction terms were interpreted as evidence of associations of the biomarker with postnatal growth (PG) trajectory. Marginal effects at discrete ages were estimated based on the fitted model. Results25OHD was associated with PG (P = 0.022), with a negative association with LAZ at birth, but no association at subsequent time points. IGF1 and RANKL were both significantly associated with PG (pIGF1 < 0.001; pRANKL = 0.022), were not associated with LAZ at birth, but were positively associated with LAZ at subsequent time points. OC was associated with PG (P < 0.001), was negatively associated with LAZ at birth, and was positively associated with LAZ at 12 months. NT-proCNP was associated with postnatal LAZ trajectories (P < 0.001), with negative associations with LAZ at 3 and 6 months of age, but no association at 12 months. There was no significant association between FGF21 and PG; however, FGF21 was consistently negatively associated with LAZ. OPG and FGF23 were not associated with PG. ConclusionsSeveral serum/plasma biomarkers were associated with infant linear growth in a cohort from Bangladesh. IGF1, RANKL, and OC were most strongly associated postnatal LAZ growth. FGF21 was not associated with PG but was associated with fetal linear growth with sustained effects in the postnatal period. Funding SourcesFunded by the Bill and Melinda Gates Foundation.

Dynamics of serum C-type natriuretic peptide as predictor for preeclampsia.

To evaluate serum levels of the amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) in uneventful pregnancies and pregnancies complicated by preeclampsia (PE) and NTproCNP's accuracy for prediction of PE. Nested case control pilot study including women with uneventful pregnancy (Control, n = 100) and asymptomatic women who later developed PE (PE_long, n = 12). NTproCNP levels were measured in a maximum of ten sequential blood samples per patient (seven visits during pregnancy, three afterwards), which had been collected prospectively. In controls, NTproCNP decreased from weeks 11-13 on, reaching a nadir at the end of the second trimester (weeks 23-27), and subsequently reached the highest levels at the end of pregnancy. In comparison, the PE_long group showed a significantly different NTproCNP course (p = .042), including significantly elevated levels in weeks 18-22 (p = .034) and 23-27 (p = .016). Significant predictive power of single time point measurements of NTproCNP for predicting short-term occurrence of preeclampsia in asymptomatic women was found in weeks 28-32 (p = .023) and 33-36 (p = .014). Furthermore, an increase > -0.038 pmol/l per week between weeks 11-13 and 14-17 was also predictive for PE (area under the curve, AUC: 0.75; p < .001; sensitivity: 90%; specificity: 60%), as was an increase of > 0.084 pmol/l per week between weeks 11-13 and 18-22 (AUC: 0.69, p = .048; sensitivity: 55%; specificity: 88%). Measurement of NTproCNP in pregnancy might be useful to increase diagnostic awareness in women who will develop PE.

Postnatal effects of intrauterine treatment of the growth-restricted ovine fetus with intra-amniotic insulin-like growth factor-1.

Fetal growth restriction increases the risk of fetal and neonatal mortality and morbidity, and contributes to increased risk of chronic disease later in life. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of the growth-restricted ovine fetus improves fetal growth, but postnatal effects are unknown. Here we report that intra-amniotic IGF1 treatment of the growth-restricted ovine fetus alters size at birth and mechanisms of early postnatal growth in a sex-specific manner. We also show that maternal plasma C-type natriuretic peptide (CNP) products are related to fetal oxygenation and size at birth, and hence may be useful for non-invasive monitoring of fetal growth restriction. Intrauterine IGF1 treatment in late gestation is a potentially clinically relevant intervention that may ameliorate the postnatal complications of fetal growth restriction. Placental insufficiency-mediated fetal growth restriction (FGR) is associated with altered postnatal growth and metabolism, which are, in turn, associated with increased risk of adult disease. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of ovine FGR increases growth rate in late gestation, but the effects on postnatal growth and metabolism are unknown. We investigated the effects of intra-amniotic IGF1 administration to ovine fetuses with uteroplacental embolisation-induced FGR on phenotypical and physiological characteristics in the 2 weeks after birth. We measured early postnatal growth velocity, amino-terminal propeptide of C-type natriuretic peptide (NTproCNP), body composition, tissue-specific mRNA expression, and milk intake in singleton lambs treated weekly with 360μg intra-amniotic IGF1 (FGRI; n=13 females, 19 males) or saline (FGRS; n=18 females, 12 males) during gestation, and in controls (CON; n=15 females, 22 males). There was a strong positive correlation between maternal NTproCNP and fetal oxygenation, and size at birth in FGR lambs. FGR lambs were ∼20% lighter at birth and demonstrated accelerated postnatal growth velocity. IGF1 treatment did not alter perinatal mortality, partially abrogated the reduction in newborn size in females, but not males, and reduced accelerated growth in both sexes. IGF1-mediated upregulation of somatotrophic genes in males during the early postnatal period could suggest that treatment effects are associated with delayed axis maturation, whilst treatment outcomes in females may rely on the reprogramming of nutrient-dependent mechanisms of growth. These data suggest that the growth-restricted fetus is responsive to intra-amniotic intervention with IGF1, and that sex-specific somatotrophic effects persist in the early postnatal period.

Plasma Amino-Terminal Propeptide of C-Type Natriuretic Peptide Concentration in Normal-Weight and Obese Children.

Objective:In studies on the relationship between amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) concentration and height velocity in children, CNP has been implicated as an emerging new growth marker during childhood. It has been reported that besides its well-studied role in growth, plasma CNP levels are reduced in overweight and/or obese adolescents, suggesting CNP as a potential biomarker in childhood obesity. The primary goal of this study was to test this hypothesis in a Turkish population.Methods:Consent was taken from 317 children [ages 0-18 (158 girls, 159 boys)] and their parents. All subjects were physically examined; anthropometric measurements were obtained. Body mass index was calculated. During routine blood work, 1 mL extra blood was taken. Plasma NT-proCNP concentration was measured by enzyme-linked immunosorbent assay.Results:Results confirmed the previously described relationship between plasma NT-proCNP concentration and growth velocity. Plasma NT-proCNP concentration showed a negative correlation with age, weight, and height in children. Gender was not a factor that alters the age-dependent plasma NT-proCNP concentration until puberty.Conclusion:Unlike previous reports, plasma NT-proCNP concentration of overweight/obese children was not significantly lower than that of children with normal weight in age groups analyzed in a Turkish population. Thus, it is too early to conclude that CNP is a potential biomarker in childhood obesity. Further studies are necessary to address this question.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. This was a longitudinal cohort study. Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. Serum NT-proCNP levels and height were measured. NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.

The alteration of NTproCNP plasma levels following anaerobic exercise in physically active young men.

Objective:Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) is a synthesis product of C-type natriuretic peptide (CNP). In this study, plasma levels of NTproCNP were compared before and after exercise in healthy young subjects who are physically active (PA) or not physically active (NPA).Methods:The study was carried on PA group (n=10) who defined the exercise duration more than 2.5 hours per week for at least one year and NPA group (n=10) whose exercise duration was lower than 1.5 hours per week. The level of maximal oxygen consumption was determined. Wingate exercise test was applied on the following day. Plasma NTproCNP levels were measured before the exercise and at the 1st, 5th and 30th minute after the exercise.Results:Exercise duration of physically active group was reported as 11.3±5.0 hours per week. Basal NTproCNP levels of the groups were found to be comparable. NTproCNP levels in the 5th minute (0.93±0.23 pmol/L; p<0.05) and in the 30th minute (0.77±0.21 pmol/L p<0.05) after exercise were higher than the levels before exercise (0.64±0.29 pmol/L) in PA group. Additionally, the plasma levels of NTproCNP after 5th minute of exercise were higher in PA group (0.93±0.23 pmol/L) than NPA group (0.74±0.16 pmol/L, p<0.05).Conclusion:Being physically active may be a fact affecting the secretion of CNP, which plays a protective role in endothelium, following exercise.

Impact of vitamin D supplementation on markers of bone mineral metabolism in term infants

25-Hydroxyvitamin D (25OHD) may influence bone turnover. We compared the dynamics of bone markers in 30 infants on vitamin D supplementation (≅550IU/day) with different degrees of hypovitaminosis D (25OHD <11ng/ml — deficiency vs. ≥11 <20ng/ml — insufficiency). Baseline and follow-up (after 10weeks), 25OHD, 1,25-dihydroxyvitamin D (1,25(OH)2D), alkaline phosphatase (ALP), PTH, osteocalcin (OC), N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX), and amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) were measured. None of the newborns had craniotabes, hypocalcemia or hyperparathyroidism. The median (Q1;Q3) 25OHD increased from a baseline of 8.45 (7;11.9) ng/ml to 54.6 (34.7;67.3) ng/ml (p<0.001). The baseline 25OHD negatively correlated with total increment of 25OHD (r=−0.54; p=0.002). There were changes in ALP (241 vs. 331IU; p<0.001), 1,25(OH)2D (48 vs. 95.5pg/ml, p<0.001), OC (88.8 vs. 159.1ng/ml, p<0.001), PINP (3886 vs. 2409ng/ml; p<0.001), CTX (1.6 vs. 1.1ng/ml; p<0.001), and NT-proCNP (75.1 vs. 35.1pmol/l; p<0.001). Vitamin D deficient infants at baseline, compared to the insufficient group, revealed significantly higher percentage changes for 25OHD (745% vs. 167%, p<0.0001), OC (113% vs. 40%, p<0.05) and 1,25(OH)2D (95% vs. 58%, p<0.05). Conclusions: Vitamin D supplements had little to no impact on markers of bone turnover in term infants in the first few months of life, with the exception of osteocalcin. Ten weeks of cholecalciferol supplementation at a dose of 550IU/day led to a marked increase of 25OHD concentration. The magnitude of 25OHD increment was inversely related to vitamin D status at baseline. Irrespective of the severity of vitamin D deficiency, a secondary hyperparathyroidism with elevated iPTH, ALP, phosphaturia or hypophosphatemia was not observed in the studied neonates.

Role of C-type Natriuretic Peptide in Linear Growth

The natriuretic peptides are a family of three peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). CNP is produced in the growth plate and acts in a paracrine/autocrine manner and has been found to play an essential role in enchondral bone growth , as demonstrated in rodents and human. Biosynthetic processing of CNP releases a bioinactive amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) and is produced in equimolar amounts with CNP. The level of NTproCNP in plasma reflects the rate of CNP biosynthesis and measured easily using commercial kit by enzyme-linked immunosorbent assay (ELISA) method. Knockout mice for CNP or its cognate receptor (NPR-B) are dwarfed. In human, homozygous loss of functional mutations in the NPR-B gene causes acromesomelic dysplasia, Maroteaux type (OMIM #602875). To clarify the role of CNP/NTproCNP in linear growth in human, some researchers measured plasma NTproCNP levels in healthy children and children with short stature due to various causes. CNP showed the heighest levels after 12 hr of life and with a progressive decline afterwards. It is proved that there is modest but significant correlation between NTproCNP level and IGF-I in healthy children and the timing of peaks in NTproCNP and IGF-I were identical in both sex. This paper will introduce recent advances of researches concerning about the role of CNP/NTproCNP in human growth in children with various conditions and suggest the future direction of this promising study field.

Changes of amino-terminal propeptide of C-type natriuretic peptide and growth velocity in patients with idiopathic short stature or isolated growth hormone deficiency after recombinant human growth hormone treatment

Objective To explore the value of amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) in evaluating the efficacy of therapy with recombinant human growth hormone ( rhGH ) in patients with idiopathic short stature (ISS) and isolated growth hormone deficiency ( IGHD ).Methods Forty-eight prepubertal children( IGHD n=25,ISS n=23 ) treated for at least 1 year with rhGH were included.Serum insulin-like growth factor- Ⅰ ( IGF- Ⅰ ) and NTproCNP levels were measured before starting treatment and 6 months later.Twelve months after starting treatment,all patients were assessed and annual growth velocity ( GV ),height standard deviation score ( HTSDS),and gained HTSDS (△HTSDS) were recorded.Results In GHD group,positive relationships between GV and change of IGF- ISDS( △IGF- ISDS ),GV and change of NTproCNP concentrations(△NTproCNP) were found( r=0.407,P=0.044 ;r=0.490,P=0.013 ).GH peak value was also positively associated with IGF- ISDS and NTproCNP before therapy ( r =0.558,P =0.004; r =0.630,P =0.001 ).△IGF- ISDS and △NTproCNP were positively associated after therapy ( r =0.466,P =0.019 ).In ISS group,GV was associated with △NTproCNP ( r=0.845,P＜ 0.01 ).Conclusions NTproCNP is a novel biomarker of growth as its level increases during growth-promoting treatment.Furthermore,IGF- Ⅰ is also valuable in evaluating the efficacy of rhGH therapy in short stature patients. Key words: Growth hormone treatment; Growth hormone deficiency; Idiopathic short stature; Insulinlike growth factor- Ⅰ ; C-type natriuretic peptide

P16 Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP): reference range and levels in children with idiopathic short stature treated with growth hormone

P16 Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP): reference range and levels in children with idiopathic short stature treated with growth hormone