Recombinant human growth hormone treatment for dilated cardiomyopathy in children.

OBJECTIVE: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure among children and is often progressive despite maximal medical therapy. Heart failure is characterized by a number of neurohormonal abnormalities, including derangements in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling axis. Decreased serum levels of GH, which acts on cardiac myocytes primarily through IGF-1, are associated with impaired myocardial growth and function, which can be improved with restoration of GH/IGF-1 homeostasis. In animal models and among human adults with heart failure attributable to DCM, treatment with GH results in acquisition of left ventricular (LV) mass and improved LV function, through a combination of mechanisms. We undertook this study to determine the effects of recombinant human GH on LV function and mass among children with stable LV dysfunction attributable to DCM. METHODS: We performed a prospective, single-center, randomized, partially blinded, crossover trial among children 1 to 19 years of age with DCM and cardiac dysfunction of > or =6-month duration. After enrollment, patients were randomly assigned to receive treatment for 6 months with either conventional therapy (determined by the patient's primary cardiologist) plus recombinant human GH (0.025-0.04 mg/kg per day), administered as daily subcutaneous injections, or conventional therapy alone. Patients were then crossed over to the other treatment strategy for 6 months. The primary outcome measure was change in LV shortening fraction (SF). Other echocardiographic indices of LV function, somatic growth, and somatotropic/thyroid hormone levels were also monitored. RESULTS: Only 8 of an intended 15 patients were enrolled, because of a combination of factors. Two patients withdrew during the study as a result of declining LV function requiring transplantation. LV SF did not change significantly during GH treatment, although both LV SF and LV SF z score were higher 6 months after cessation of GH treatment than at baseline. LV ejection fraction increased during GH therapy to a degree that approached significance. Height and weight percentiles for age increased significantly during GH therapy and remained higher 6 months after treatment. Annualized height velocity during GH treatment (13.7 +/- 3.3 cm/year, >97th percentile for all patients) was significantly higher than that after GH discontinuation (3.2 +/- 3.5 cm/year). Serum levels of IGF-1 and IGF-binding protein-3 were significantly higher after 6 months of GH treatment and 6 months after discontinuation of GH treatment than at baseline. There were no adverse events related to GH treatment. DISCUSSION: In this prospective, single-center, randomized, partially blinded, crossover trial, recombinant human GH was administered to 8 pediatric patients with stable chronic heart failure secondary to DCM. Because of unanticipated difficulty enrolling eligible patients, the study was underpowered to detect changes in our primary outcome measure of the magnitude we projected. Nevertheless, we did observe several notable cardiovascular effects of GH treatment, including a trend toward improved LV ejection fraction during the course of GH treatment and significantly improved LV SF, SF z score, and LV end systolic stress z score 6 months after discontinuation of GH treatment (relative to baseline values). Given the fact that levels of IGF-1, the primary myocardial effector of GH signaling, remained significantly higher 6 months after GH treatment than at baseline, the improvement in LV functional indices 6 months after discontinuation of therapy may represent progression or perpetuation of a GH treatment effect. In addition to its cardiovascular effects, GH therapy was associated with significant acceleration of somatic growth. The benefits of GH were not associated with significant attributable side effects, although 2 patients developed progressive LV dysfunction during the study and underwent cardiac transplantation.

Effect of prenatal diagnosis on outcomes in D-transposition of the great arteries.

BACKGROUND: By decreasing preoperative morbidity, prenatal diagnosis could improve neurodevelopmental outcomes in infants with critical congenital heart disease. We explored the impact of prenatal diagnosis on perinatal and perioperative variables and on outcomes at 1 year of age. METHODS: We analyzed a database of children enrolled in prospective studies on surgical support techniques from 1988 to 2000. Selection criteria included a diagnosis of D-transposition of the great arteries with intact ventricular septum or ventricular septal defect, no extracardiac congenital anomalies, birth weight >2.3 kg, and repair by arterial switch procedure. RESULTS: Of 346 patients at enrollment, 25 had a prenatal diagnosis, and 321 did not. Children with prenatal diagnosis, compared with those without, had a lower likelihood of birth by spontaneous labor, lower birth weights, lower Apgar 5 scores, a higher rate of preoperative endotracheal intubation, and surgery at a younger age. They tended to have a lower incidence of fetal distress during labor. At 1 year of age, 272 patients were tested with the Psychomotor Development Index and Mental Development Index of the Bayley Scales. Mean z scores were similar in those with and without prenatal diagnosis for both Psychomotor Development Index (-0.92 +/- 0.93 vs -0.88 +/- 1.05) and Mental Development Index (-0.29 +/- 1.13 vs -0.41 +/- 0.93). CONCLUSIONS: Infants with D-transposition of the great arteries with and without prenatal diagnosis differed with respect to perinatal and perioperative variables, but their development at 1 year of age was similar. Future studies should include a greater number of children with prenatal diagnosis and a variety of congenital heart lesions.