Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected]

We report that the dominant human missense mutations G303E and G296S in GATA4, a cardiac-specific transcription factor gene, cause atrioventricular septal defects and valve abnormalities by disrupting a signaling cascade involved in endocardial cushion development. These GATA4 missense mutations, but not a mutation causing secundum atrial septal defects (S52F), demonstrated impaired protein interactions with SMAD4, a transcription factor required for canonical bone morphogenetic protein/transforming growth factor-ß (BMP/TGF-ß) signaling. Gata4 and Smad4 genetically interact in vivo: atrioventricular septal defects result from endothelial-specific Gata4 and Smad4 compound haploinsufficiency. Endothelial-specific knockout of Smad4 caused an absence of valve-forming activity: Smad4-deficient endocardium was associated with acellular endocardial cushions, absent epithelial-to-mesenchymal transformation, reduced endocardial proliferation, and loss of Id2 expression in valve-forming regions. We show that Gata4 and Smad4 cooperatively activated the Id2 promoter, that human GATA4 mutations abrogated this activity, and that Id2 deficiency in mice could cause atrioventricular septal defects. We suggest that one determinant of the phenotypic spectrum caused by human GATA4 mutations is differential effects on GATA4/SMAD4 interactions required for endocardial cushion development.

Hemodynamic responses to etomidate on induction of anesthesia in pediatric patients.

Etomidate is often used for inducing anesthesia in patients who have limited hemodynamic reserve. Using invasive hemodynamic monitoring, we studied the acute effects of a bolus of etomidate during induction of anesthesia in children. Twelve children undergoing cardiac catheterization were studied (mean age, 9.2 +/- 4.8 yr; mean weight, 33.4 +/- 15.4 kg); catheterization procedures included device closure of secundum atrial septal defects (n = 7) and radiofrequency catheter ablation procedures for supraventricular tachycardia (n = 5). Using IV sedation, a balloon-tipped pulmonary artery catheter was placed to measure intracardiac and pulmonary artery pressures and oxygen saturations. Baseline measurements were recorded and then repeated after a bolus of IV etomidate (0.3 mg/kg). For the entire group, no significant changes in right atrial, aortic, or pulmonary artery pressure, oxygen saturations, calculated Qp:Qs ratio or systemic or pulmonary vascular resistance were detected after the bolus dose of etomidate. The lack of clinically significant hemodynamic changes after etomidate administration supports the clinical impression that etomidate is safe in children. Further research is needed to determine the hemodynamic profile of etomidate in neonates and in pediatric patients with severe ventricular dysfunction and pulmonary hypertension.

Cardiac surgery in a child with sacral and intrasacral haemangioma.

A 23-month-old female with giant sacral (S1-S5) and intrasacral (L4-S5) haemangioma, lipomyeloschisis and a tethered cord presented for correction of a sinus venosus atrial septal defect. Angiography revealed a large perisacral hypervascular mass with large veins and an intraspinal extension. The patient had a neurogenic bladder and left extremity weakness due to spinal cord compression. The potential for additional neurological injury secondary to bleeding, venous congestion, ischaemia and steal phenomenon during cardiopulmonary bypass is discussed.