Growth hormone and its mediator, insulinlike growth factor 1 (IGF-1), are key determinants of growth in children and young adults. As patients with Fontan physiology often experience diminished longitudinal growth, we sought to describe IGF-1 levels in this population and to identify factors associated with IGF-1 deficiency. Forty-one Fontan subjects ≥5 years were evaluated in this cross-sectional study. Age- and gender-specific height Z scores were generated using national data. Laboratory testing included IGF-1 and brain natriuretic peptide (BNP) levels. IGF-1 levels were converted to age-, gender-, and Tanner stage–specific Z scores. BNP levels were log transformed to achieve a normal distribution (log-BNP). Medical records were reviewed for pertinent clinical variables. Predictors of IGF-1 Z score were assessed through the Student t test and Pearson’s correlation. Median age was 11.1 years (range 5.1 to 33.5 years), and time from Fontan was 8.2 years (1.1 to 26.7). Mean height Z score was −0.2 ± 0.9 with a mean IGF-1 Z score of −0.1 ± 1.3. There was no association between IGF-1 Z score and height Z score. Longer interval since Fontan ( R = −0.32, p = 0.04), higher log-BNP ( R = −0.40; p = 0.01), and lower indexed systemic flow on cardiac magnetic resonance ( R = 0.55, p = 0.02) were associated with lower IGF-1 Z scores. In conclusion, in this cohort with Fontan physiology, higher BNP and lower systemic flow were associated with lower IGF-1 Z score. Longitudinal studies are needed to determine if these relations represent a mechanistic explanation for diminished growth in children with this physiology and with other forms of congenital heart disease.
The Fontan operation is the final stage of palliation for various forms of single ventricle heart disease. In the 4 decades since its initial description, life expectancy of patients who have undergone the Fontan operation has improved dramatically and attention has shifted toward the noncardiac sequelae of a circulation characterized by increased central venous pressure and diminished cardiac output. Longitudinal growth impairment is well recognized following the Fontan procedure. However, the underlying causes of impaired growth in this population are poorly understood. Growth hormone (GH) and its mediator, insulinlike growth factor 1 (IGF-1), are fundamentally important to linear growth in children whether they have congenital heart disease. The pituitary gland releases GH in response to a hypothalamic signal; GH stimulates the production of IGF-1 in the liver and locally within target organs. Both GH and IGF-1 act on the chondrocyte growth plate to stimulate longitudinal growth. Disruptions in this pathway have been implicated in growth impairment in other pediatric chronic diseases. Emerging evidence suggests that the GH/IGF-1 pathway may also be abnormal in children with congenital heart disease, but existing studies are limited by their small number of patients with single ventricle heart disease. The goals of this study were to describe IGF-1 levels in children and young adults after Fontan palliation, to correlate IGF-1 levels with growth parameters, and to identify risk factors for low IGF-1 levels to increase understanding of the underlying causes of growth failure in these patients.
Methods
Fifty Fontan participants aged ≥5 years were prospectively enrolled in a single-center cross-sectional study of growth, nutrition, body composition, and bone health from July 2011 through October 2013, as previously described. All Fontan patients followed by the center were eligible and were contacted for potential study participation. Exclusion criteria included the following: pregnancy, metal hardware that prevented dual-energy x-ray absorptiometry (as this was included in the original study protocol), Fontan baffle obstruction or single lung physiology, moderate-to-severe chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m 2 ), moderate-to-severe hepatic impairment (transaminases >2 times the upper limit of normal), and inability to complete the study procedures because of developmental delay. The data presented here exclude the 4 participants with protein-losing enteropathy (PLE), 2 with genetic syndromes potentially impacting growth, and an additional 3 with missing IGF-1 levels.
The study protocol was approved by the Institutional Review Board at The Children’s Hospital of Philadelphia. Informed consent was obtained from participants aged >18 years and assent as well as parental consent from those <18 years.
Pertinent variables including cardiac anatomy, ventricular morphology, presence of heterotaxy syndrome, date and type of Fontan procedure, and presence of a fenestration at initial operation were obtained through patient interviews and confirmed in the medical record. Oxygen saturation and hemoglobin were obtained from the medical record when available.
Anthropometric measures were obtained in light clothing with shoes removed. Weight (0.1 kg) was measured using a digital scale (Scaltronix, White Plains, New York). Height (0.1 cm) was measured using a stadiometer (Holtain Ltd, Croswell, Crymych, United Kingdom). Pubertal status (Tanner stage) was assessed with a validated self-assessment questionnaire.
Serum brain natriuretic peptide (BNP) was measured using a chemiluminescent microparticle immunoassay. The lower limit of detection for our laboratory is 10 pg/ml; patients with levels <10 pg/ml were assigned a level of 10. IGF-1 was measured by Esoterix Laboratory Services (Calabasas Hills, California) using a radioimmunoassay. IGF-1 levels were converted to gender-, age-, and Tanner stage–adjusted Z scores using Esoterix laboratory’s reference data. Adult participants were considered to be 18 years old.
Echocardiography was performed on a Phillips IE33 machine (Phillips, Andover, Massachusetts) according to our standard imaging protocol. Ventricular function and atrioventricular valve regurgitation were qualitatively assessed. Cardiac magnetic resonance (CMR) studies were performed on a 1.5-T Avanto Magnetic Resonance Imaging scanner (Siemens Medical Solutions, Erlangen, Germany) with a 6-channel phased-array body coil using a standard imaging protocol. Phase-contrast velocity mapping was used to determine systemic blood flow (Qs) by measuring summed caval flow. Ventricular volumes and Qs were indexed to body surface area.
Continuous variables were expressed as means ± standard deviation or median (range). The 2000 National Center for Health Statistics growth data were used to calculate gender-specific Z scores for height and BMI, relative to age. Participants aged >20 years at the time of the study visit were assigned an age of 20 years for the generation of height Z scores. BMI Z scores were calculated in those aged <20 years. The distribution of BNP was highly skewed in favor of lesser values, so these values were normalized with natural logarithmic transformation (log-BNP). The associations between IGF-1 Z scores and Fontan clinical characteristics were examined using Pearson correlation for continuous variables and by comparisons of Z scores (Student t test) according to categorical variables such as the presence of a systemic right ventricle. Demographic and clinical characteristics were compared between those with IGF-1 Z scores greater than and less than the median Z score using Student t test and chi-square analysis. Of note, IGF-1 Z scores were not associated with lean body mass Z scores in our previous report in this cohort. Analyses were performed using Stata 12.0 (Stata Corp., College Station, Texas). A p value <0.05 was considered significant and 2-sided tests were used throughout.
Results
Demographic and anthropometric characteristics of the participants are summarized in Table 1 . Height Z score did not vary with age or interval since the Fontan procedure. The disease-specific characteristics of the 41 Fontan participants are summarized in Table 2 . CMR data were available on 17 participants and are summarized in Table 3 . Median BNP level was 17.5 (range 10 to 247, interquartile range 17.9). Thirty-three of the participants (80%) had a BNP level <40, whereas 39 (95%) had a BNP level <100. Ten participants (24%) had a BNP level <10 pg/ml, the lower limits of detection for our laboratory.
| Variable | Value |
|---|---|
| Age, median (range) (year) | 11.1 (5.1-33.5) |
| Interval from Fontan, median (range) (year) | 8.2 (1.1-26.7) |
| Male | 21 (51%) |
| White | 29 (71%) |
| Black | 5 (12%) |
| Other | 7 (17%) |
| Tanner stage 1-2 | 22 (54%) |
| Height Z-score, mean ± SD | -0.2 ± 0.9 |
| Range | -2.5 to 1.0 |
| Body mass index Z-score, mean ± SD ∗ | 0.1 ± 0.9 |
| Range | -2.5 to 2.2 |
| Insulin-like growth factor-1 Z-score, mean ± SD | -0.1 ± 1.3 |
| Range | -2.7 to 3.0 |
| Variable | Value | p value for association with IGF-1 Z-score |
|---|---|---|
| Anatomy | 0.71 | |
| Hypoplastic left heart syndrome | 13 (32%) | |
| Tricuspid atresia | 7 (17%) | |
| Unbalanced atrioventricular canal defect | 7 (17%) | |
| Other single ventricle variants | 6 (15%) | |
| Double outlet right ventricle | 6 (15%) | |
| Pulmonary atresia/intact ventricular septum | 2 (4%) | |
| Heterotaxy syndrome | 4 (10%) | 0.55 |
| Ventricular morphology | 0.09 | |
| Right ventricle | 17 (42%) | |
| Left ventricle | 14 (34%) | |
| Mixed | 10 (24%) | |
| Type of Fontan | 0.05 | |
| Extracardiac-conduit | 26 (63%) | |
| Lateral tunnel | 15 (37%) | |
| Fenestration ∗ | 34 (83%) | 0.1 |
| Systemic oxygen saturation † | 0.95 (0.85-0.99) | 0.19 |
| Hemoglobin (g/dL) ‡ | 14.4 (12.6-18.6) | 0.72 |
| Brain type natriuretic peptide, (pg/mL) median (range, interquartile range) | 17.5 (10-247;17.9) | 0.01 |
| Echocardiographic assessment § | ||
| Normal or low normal ventricular function | 31 (84%) | 0.9 |
| Absent or mild atrioventricular valve regurgitation | 32 (86%) | 0.99 |
∗ at time of initial operation.
| Variable | Value | R value for association with IGF-1 Z-score | p value for association with IGF-1 Z-score |
|---|---|---|---|
| Ejection fraction (%) | 65 ± 10 | 0.01 | 0.97 |
| End-diastolic volume (cc/m 2 ) | 82 ± 25 | 0.24 | 0.35 |
| End-systolic volume (cc/m 2 ) | 30 ± 15 | 0.18 | 0.49 |
| Stroke volume (cc/m 2 ) | 52 ± 15 | 0.23 | 0.37 |
| Summed caval flow (L/min/m 2 ) | 2.4 ± 0.5 | 0.55 | 0.02 |
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