Growth hormone and the heart in children

Abstract

Background and Aims: The fact that growth hormone (GH) influences cardiovascular structure and function is well established through both human and animal studies. Despite being secreted in a pulsatile fashion, only the impact of peak GH concentrations on cardiac parameters has previously been reported, and the time-dependency of cardiovascular effects during GH treatment has not been detailed. The aims of this pediatric study were (i) to establish the expression of GH-receptor (GH-R) and insulin-like growth factor I (IGF-I) mRNA locally in the heart in children of different ages, (ii) to study in detail the relationship between the heart and endogenous GH secretion pattern, (iii) to study the cardiovascular effects of GH treatment and (iv) to examine organ/tissue-specific responses to GH. Patients & Methods: Two trials were conducted. In the first, a cardiac biopsy was taken from 18 children undergoing heart surgery. GH-R and IGF-I mRNA were quantified by real-time polymerase chain reaction. In the second trial, 153 short prepubertal children were randomized to receive either a standard or an individualized GH dose. Echocardiography, blood pressure measurements and electrocardiography were performed at study start, and after 3 months, 1 year and 2 years of GH treatment. Results: GH-R and IGF-I mRNA was found in all children studied. There was a significant relationship between their relative amounts (r=0.75, p<0.001), and body mass index was correlated with the relative expression of both genes (r=0.59, p=0.01 and r=0.50, p=0.04 respectively). Cardiac dimensions were not correlated with peak endogenous GH concentration but were negatively correlated with GH trough levels (r= –0.41, p<0.001) and positively correlated with GH secretion rate above baseline level (r=0.44, p<0.001). During treatment, a biphasic, time-dependent, cardiac response was seen. Initially, there was an increase in both standard deviation scores (SDS) for left ventricular (LV) diameter in diastole SDS (95% confidence interval (CI) for the increase in SDS from baseline to 3 months (ΔLVDdSDS0–3m): 0.05 to 0.36) and LV wall thickness, exemplified by septal thickness (ΔIVDdSDS0–3m: 95% CI 0.08 to 0.54). At 2 years, wall thickness returned to baseline values (ΔIVDdSDS0–24m: 95% CI -0.41 to 0.06) but LV diameter remained increased (ΔLVDdSDS0–24m: 95% CI 0.19 to 0.47). The heart was also found to be more responsive than both skeletal muscle and bone tissue to GH treatment. The dose resulting in a 50% response (ED50%) was as low as 33 µg/kg/d (90% confidence bounds: 24–38 µg/kg/d)) for LVDd compared with an ED50% of 51 (47–56) µg/kg/d for longitudinal growth and 57 (52–65) µg/kg/d for IGF-I. Conclusion: With the presence of local GH-R and high sensitivity of the heart to GH, cardiac tissue is a primary target for GH. The GH trough levels seem to be of greater importance for cardiac dimensions than the peak GH concentrations, and the response to GH treatment is time-dependent