ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Tsung-Po Tsai
Jung-Min Yu
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsai, T.-P.
Right arrow Articles by Chen, F.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsai, T.-P.
Right arrow Articles by Chen, F.-L.
Related Collections
Right arrow Congenital - acyanotic
Right arrowRelated Article

Ann Thorac Surg 2002;73:1765-1768
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Change of serum growth factors in infants with isolated ventricular defect undergoing surgical repair

Tsung-Po Tsai, MD*a, Jung-Min Yu, MDa, Yi-Liang Wu, MDa, Chih-Yang Huang, PhDb, Fong-Lin Chen, MDc

a Division of Cardiovascular Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan, China
b Division of Biochemistry, Chung Shan Medical University and Hospital, Taichung, Taiwan, China
c Division of Pediatric Cardiology, Chung Shan Medical University and Hospital, Taichung, Taiwan, China

Accepted for publication February 4, 2002.

* Address reprint requests to Dr Tsai, No. 110, Sec l, Chien-Kuo N. Road, Taichung, Taiwan, China
e-mail: tsai{at}csh.org.tw


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Despite increasing clinical use and recent evidence that insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and human growth hormone (hGH) target the heart, the clinical manifestations following the change in the serum growth factors in infants with isolated ventricular septal defect (VSD) undergoing surgical repair have not been clearly defined.

Methods. Twenty normal infants (group I) and 44 consecutive infants with echocardiography established isolated VSD (aged from 3 months to 1 year; body weight from 6.0 ± 1.8 kg to 8.2 ± 1.6 kg) were investigated. Among 44 infants with VSD, 20 with shunt fraction, Qp/Qs <=1.5 were free of symptoms of congestive heart failure (group II); 24 with shunt fraction, Qp/Qs >=2.0 were in congestive heart failure (group IIIa); and 20 of these 24 infants had undergone VSD repair 6 months before their second study (group IIIb). Serum IGF-1, IGFBP-3, and hGH factors were determined by enzyme-linked immunosorbent assay using a monoclonal antibody.

Results. The serum levels of IGF-1, IGFBP-3, and hGH factors were 111.9 ± 2.3 ng/mL, 22.0 ± 2.3 ng/mL, and 3.6 ± 0.7 µIU/mL for group I; 63.8 ± 8.2 ng/mL, 17.1 ± 1.6 ng/mL, and 4.1 ± 1.2 µIU/mL for group II; 24.0 ± 2.6 ng/mL, 9.4 ± 0.7 ng/mL, and 14.7 ± 3.5 µIU/mL for group IIIa; 79.4 ± 12 ng/mL, 20.3 ± 1.3 ng/mL, and 4.3 ± 0.7 µIU/mL for group IIIb. In comparison to group I, the decrease in serum levels of IGF-1 and IGFBP-3 in groups II and IIIa were statistically significant (in group II 43% and 32%, p < 0.05; in group IIIa 79% and 37%, p < 0.01). Also the increase in serum level of hGH concentration in group IIIa was significant (increased threefold, p < 0.01). Interestingly, the change in serum levels of IGF-1, IGFBP-3 (decrease), and hGH (increase), returned to the normal range of serum levels after VSD repair in group IIIb. All congestive heart failure symptoms subsided in group IIIb during follow-up.

Conclusions. Improvement in serum levels of IGF-1, IGFBP-3, and hGH were identified in infants with VSD after surgical repair.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Insulin-like growth factor-1 (IGF-1) is a growth hormone (hGH)-dependent peptide that plays an important role in tissue growth and differentiation [1]. Insulin-like growth factor binding protein-3 (IGFBP-3) represents the major IGF-1-binding protein in serum and acts to maintain a circulatory store of IGF-1 to prevent large fluctuations in IGF-1 activity [2]. It is accepted and recognized that hGH and IGF-1 are critical for normal growth, maintenance of skeletal mass, and metabolic homeostasis in children [3]. However, it has been reported that patients with growth retardation and congenital heart disease often have elevated, rather than decreased, levels of plasma hGH [4]. One possible explanation for this paradox is the observation made by Barton and associates [4] that infants in nutritional deficiency often suffer from growth retardation and congenital cardiac defects, and these infants exhibit growth hormone insensitivity with concomitant significant reduction in serum IGF-1 and IGFBP-3 concentrations. We sought to investigate this potential relation between serum growth factors and congenital ventricular defects by assaying the levels of hormones in normal infants and those with congenital defects before and after surgical repair. Serial measurements of serum IGF-1, IGFBP-3, and hGH may be a useful adjunct to assess and monitor the clinical prognosis and nutritional support in infants with congenital ventricular septal defect (VSD) undergoing surgical repair.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Twenty normal healthy age-matched control infants (group I) and 44 consecutive infants with echocardiography established isolated VSD (aged from 3 months to 1 year; body weight from 6.0 ± 1.8 kg to 8.2 ± 1.6 kg with a mean of 7.0 ± 0.7 kg) were investigated. They had all presented within the first year of life with either asymptomatic (group II, 20 infants) or symptomatic (group IIIa, 24 infants) congenital VSD. Those 24 infants with congestive heart failure (CHF) symptoms subsequently underwent cardiac catheterization and surgical repair. Twenty of the 24 infants who had VSD repair (group IIIb) had a second study 6 months after operation. Due to minor or major postoperative complications, 4 patients did not receive follow-up study. Evaluation of infants with isolated VSD included shunt fraction (Qp/Qs) and clinical symptoms of CHF. All subjects allowed blood samples to be drawn after obtaining informed parental consent. Patients with complex congenital abnormalities, such as tetralogy of Fallot, were excluded.

Serum growth factors were measured by enzyme-linked immunosorbent assay using a monoclonal antibody (IGF-1 by ELISA kit DSL-10-2800; IGFBP-3 by ELISA kit DSL-10-6600; hGH by ELISA kit IBL-MG-59121; Diagnostic Systems Laboratories, Inc, Webster, TX). Normal values for serum IGF-1 and IGFBP-3 were obtained from the group of healthy age-matched control infants (group I).

The data were expressed as mean ± standard error of the mean. Differences among the groups were determined by one-way analysis of variance. Fisher’s least significant difference test was used to determine differences.

The study was approved by the research ethics committee of The Chung-Shan Medical University Hospital, and parental consent was obtained for all patients.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
The clinical characteristics of 64 infants divided them into four groups: group I, healthy infants; group II, VSD with Qp/Qs <=1.5 asymptomatic; group IIIa, VSD with Qp/Qs >=2.0 symptomatic; and group IIIb, VSD status post surgical repair). The difference in characteristics (age, sex, gestation weeks, birth weights, body weight at time of study, heart rate, and respiratory rate) between each group was not statistically significant except for the body weight in group IIIa (5.1 ± 0.3 kg), which was lower than the other groups (p < 0.05) (Table 1). Differences in serum levels of total protein, albumin, and creatine kinase in each group were not significant. However, a statistically significance (p < 0.05) increase in serum lactate and lower pH was noted in group IIIa. Serum IGF-1 and IGFBP-3 concentrations were reduced in infants with isolated VSD (63.8 ± 8.2 ng/mL and 17.1 ± 1.6 ng/mL in group II and 24.0 ± 2.6 ng/mL and 9.4 ± 0.7 ng/mL in group IIIa, respectively) versus normal age-matched control infants (111.9 ± 2.3 ng/mL and 22.0 ± 2.3 ng/mL in group I). Serum hGH concentration was increased threefold in infants with isolated VSD having CHF symptoms and shunt fraction (Qp/Qs) >=2.0 (14.7 ± 3.5 µIU/mL in group IIIa) versus normal control infants (3.6 ± 0.7 µIU/mL). The decrease in serum levels of IGF-1 and IGFBP-3 in groups II and IIIa were statistically significant (in group II, p < 0.05; in group IIIa, p < 0.01). Also the increase in serum level of hGH in group IIIa was significant (p < 0.01). The serum concentrations of IGF-1, IGFBP-3, and hGH in group IIIa returned to normal range after VSD repair in (group IIIb) (Table 2). There were no significant differences between groups IIIb and I in serum concentrations of IGF-1, IGFBP-3, and hGH (p < 0.05). None of the patients were nutritionally deficient. However, the growth rate change in group IIIb increased considerably (average body weight, +32%; average body length, +21%) (Fig 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics of Infants in Study

 

View this table:
[in this window]
[in a new window]
  		Table 2. Serum Levels of Growth Factors

 


View larger version (31K):
[in this window]
[in a new window]
  		Fig 1. Growth change 6 months after ventricular septal defect (VSD) repair (group IIIb).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Human growth hormone, probably acting indirectly through locally produced IGF-1, stimulates myocyte hypertrophy and increases myocyte contractility [5, 6, 7]. Insulin-like growth factor binding protein-3 is critical for the circulating IGF-1 bioactivity. Activated IGF-1 may improve the dilated cardiomyopathy and prevent heart failure [8]. The importance of hGH and IGF-1 on cardiac development is highlighted in patients with Laron syndrome, who have a genetically defective hGH signal transmission and thus do not produce circulating IGF-1 [9]. As a result, patients with Laron syndrome have decreased left ventricular stroke volume and cardiac index. Similarly, pediatric patients with VSD often exhibit growth retardation and decreased IGF-1 synthesis [10] and elevated plasma hGH [5]. The relationship between hGH and IGF-1 was elucidated by Barton and colleagues [4] who found the reduction in serum IGF-1 and IGFBP-3 concentration in infants with growth retardation and congenital cardiac defects is the result of growth hormone insensitivity. Consequently, if the cardiac defect is not corrected, the patient’s growth rate will not be normalized even if the patient received recombinant hGH [11].

In our series, the decrease in serum levels of IGF-1 and IGFBP-3 were statistically significant in group II (VSD with Qp/Qs <=1.5) and group IIIa (VSD with Qp/Qs >=2.0) (Figs 2 and 3) However, there were no significant differences in serum total protein, albumin, and creatine kinase among groups. These findings indicate that factors other than malnutrition are important in determining the circulating IGF-1 level. Insulin-like growth factor-1 is more sensitive than IGFBP-3 to growth hormone regulation [12] and this factor protects the heart from heart failure by maintaining physiologic myocardial hypertrophy [13]. It remains unclear whether the altered hormone levels in utero caused the congenital defective cardiac development or whether the hyperdynamic physiology of cardiac defects caused the altered serum growth factor level. In our study, significantly elevated serum hGH level was found in group IIIa but not in group II (Fig 4). In comparison to the gradual progressive reduction in serum IGF-1 and IGFBP-3 concentrations in groups II and IIIa, these findings indicated that the reduction of IGF-1 and IGFBP-3 in infants with VSD is not related to a disturbance in the hGH/IGF-1 axis. Infants with VSD were usually in a hyperdynamic state and sustained chronic metabolic acidosis. Elevated serum lactate levels that were caused by blood shunting through the septal defect were often identified. Because acidosis could cause a significant decrease in serum level of hGH and IGF-1 receptors [14], the chronic stress (hyperdynamic) response of IGF-1 to growth hormone might also be significantly blunted during acidosis [15]. In our study, a more significant change in pH and a lactate increase could explain the reduction in serum IGF-1 and IFGBP-3 level and the elevation in serum hGH level in group IIIa (more hemodynamic, significant VSD). However, through the positive feedback mechanism [16] by reducing the serum level of lactate and by adjusting the blood pH with VSD surgical repair, the serum levels of IGF-1, IGFBP-3, and hGH returned to the levels comparable to the normal range observed in group I.



View larger version (13K):
[in this window]
[in a new window]
  		Fig 2. Enzyme-linked immunosorbent assay analysis of insulin-like growth factor-1 (IGF-1). Data were expressed as mean ± standard error of the mean.

 


View larger version (16K):
[in this window]
[in a new window]
  		Fig 3. Enzyme-linked immunosorbent assay analysis of insulin-like growth factor binding protein-3 (IGFBP-3).

 


View larger version (14K):
[in this window]
[in a new window]
  		Fig 4. Enzyme-linked immunosorbent assay analysis of human growth hormone (hGH).

 
However, one cannot completely dismiss the possibility that altered hGH levels or sensitivity in utero may have contributed to the development of congenital cardiac defects. Sasaki and colleagues [17] found that some children with congenital cardiac defects continued to have growth retardation 2 years after surgical correction. Their growth rate was not restored until they received recombinant hGH. This implies that these children have inherent decreased sensitivity to hGH a priori to their congenital cardiac defects. As such, decreased sensitivity of cardiac myocyte to hGH may have caused incomplete ventricular septal wall closure.

Irrespective of whether hGH is the cause or effect of congenital cardiac defects, altered hGH, IGH-1, and IGFBP-3 highly suggest hemodynamic significant VSD. Normalization of these values after surgical correction correlate with the correction of the hyperdynamic state associated with VSD and the resolution of CHF.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Cittadini A., Stromer H., Katz S.E., et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat—a combined in vivo and in vitro evaluation. Circulation 1996;93:800-809.[Abstract/Free Full Text]
  2. Baxter R.C. Insulin-like growth factor binding proteins in the human circulation: a review. Hormone Res 1994;42:140-144.[Medline]
  3. Thornar M.O., Vance M.I., Horvath E., et al. The anterior pituitary. In: Wilson J.D., Foster D.W., eds. Williams’ textbook of endocrinology, 8th ed. Philladelphia: WB Saunders, 1992:221-310.
  4. Barton J.S., Hindmarsh P.C., Preece M.A. Serum insulin-like growth factor 1 in congenital heart disease. Arch Dis Child 1996;75:162-163.[Abstract]
  5. Ikkos D.D., Thanopoulos V., Ikkos D.G. 24 h plasma levels of growth hormone in growth retardation of children with congenital heart disease. Helv Paediatr Acta 1974;29:583-588.[Medline]
  6. Silverman B.L., Friedlander J.R. Is growth hormone good for heart?. J Ped 1997;131:S70-S74.[Medline]
  7. Bernstein D., Jasper J.R., Rosenfeld R.G., et al. Decreased serum insulin-like growth factor 1 associated with growth failure in newborn lambs with experimental cyanotic heart disease. J Clin Invest 1992;89:1128-1132.
  8. Osterziel K.J., Strohm O., Schuler J., et al. Randomized, double-blind, placebo controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet 1998;351:1233-1237.[Medline]
  9. Feinberg M.S., Scheinowitz M., Laron Z. Echocardiographic dimensions and function in adults with primary growth hormone resistance (Laron syndrome). Am J Cardiol 2000;85:209-213.[Medline]
  10. Soliman A.T., Madkour A., Gali M.A., et al. Growth parameters and endocrine function in relation to echocardiographic parameters in children with ventricular septal defect without heart failure. J Trop Ped 2001;47:146-152.[Abstract/Free Full Text]
  11. Rosti L., Cerini E., Festa P., et al. Lack of effects of recombinant human growth hormone in a child with a complex cardiovascular malformation and dilated cardiomyopathy. J Endocrinol Invest 2000;23:28-30.[Medline]
  12. Werner F.B., Kerstin A.W., Sten R., et al. Serum levels of insulin-like growth factor I (IGF-1) and IGF binding protein-3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 1993;76:1610-1616.[Abstract]
  13. Robert L.D., Samuel H., Hamid R.M., et al. Insulin-like growth factor-1 enhances ventricular hypertrophy, and function during the onset of experimental cardiac failure. Am Soc Clin Invest 1995;95:619-627.
  14. Ordonez F.A., Santos F., Martinez V., et al. Resistance to growth hormone and insulin-like growth factor-I in acidotic rats. Pediatr Nephrol 2000;14:720-725.[Medline]
  15. Brunnger M., Hulter H.N., Krapf R. Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone insensitivity in humans. Kidney Int 1997;51:216-221.[Medline]
  16. Stenbog E.V., Hjortdal V.E., Ravan H.B., Skjaerbaek C., Sorensen K.E., Hansen O.K. Improvement in growth, and levels of insulin-like growth factor 1 in the serum, after cavo-pulmonary connections. Cardio Young 2000;10:440-446.
  17. Sasaki H., Baba K., Nishida Y., et al. Treatment of children with congenital heart diseases and growth retardation with recombinant human growth hormone. Acta Pediatr 1996;85:251-253.[Medline]

Related Article

Invited commentary
Pedro J. del Nido
Ann. Thorac. Surg. 2002 73: 1769. [Extract] [Full Text] [PDF]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Tsung-Po Tsai
Jung-Min Yu
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsai, T.-P.
Right arrow Articles by Chen, F.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsai, T.-P.
Right arrow Articles by Chen, F.-L.
Related Collections
Right arrow Congenital - acyanotic
Right arrowRelated Article

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS