Novel and deleterious nucleotide variations in the HAND1 gene probably affect miRNA target sites and protein function in pediatric patients with congenital heart disease.

BACKGROUND: Congenital heart disease (CHD) is the most prevalent developmental defect and principal cause of infant mortality and affects cardiac and large blood vessel structures in approximately 1% of live births worldwide. To date, numerous studies have related critical genetic dysfunctions to the pathogenesis of CHDs. However, the genetic basis underlying CHD remains largely unknown. In the present study, we investigated the association of nucleotide variations in coding and noncoding regions of the HAND1 gene with the risk of CHD. The HAND1 gene, encoding a helix-loop-helix transcription factor, is particularly relevant for mechanisms underlying CHD since it plays a significant role in heart development. METHODS AND RESULTS: The genomic DNA of 150 unrelated pediatric patients with CHD was screened by PCR-SSCP and direct sequencing. Four novel and heterozygous missense mutations were identified in the first exon, with three causing amino acid substitutions (p.Val149Met, p.Tyr142His, and p.Leu146Met). In-silico analysis also indicated their deleterious impact on protein structure and function. In addition, we identified five novel nucleotide variants in the 3'UTR region (c.*461, c.*342, c.*529, c.*448, c.*593), potentially altering the target sites of miRNAs. These changes include the loss of certain target sites and the acquisition of new ones. CONCLUSIONS: These findings confirm the phenotypic association between CHDs and HAND1 mutations and can pave the way for developing new preventive and therapeutic strategies.

Pulsatile blood flow in total cavopulmonary connection: a comparison between Y-shaped and T-shaped geometry.

Single-ventricle anomaly is a hereditary heart disease that is characterized by anatomical malformations. The main consequence of this malformation is desaturated blood flow, which without proper treatment increases the risk of death. The classical treatment is based on a three-stage palliative procedure which should begin from the first few days of patient's life. The final stage is known as Fontan procedure, in which inferior vena cava is directly connected to pulmonary arteries without going through the ventricle. This connection is called total cavopulmonary connection (TCPC). After surgery, the single ventricle supplies adequate and saturated systemic blood flow to the body; however, TCPC contains low pressure and low flow pulsatility. To overcome this problem, a new method is proposed wherein pulsatile blood will be directed to the TCPC through the stenosed main pulmonary artery. In this study, through the use of Computational Fluid Dynamics, T-shaped (MRI-based) and Y-shaped (computer-generated) geometries are compared in order to determine the influence of this modification on pulsation of blood flow as well as energy loss in pulmonary arteries. The results indicate that energy loss in Y-shaped geometry is far less than T-shaped geometry, while the difference in flow pulsatility is insignificant.

Incidence and etiology of chylothorax after congenital heart surgery in children.

BACKGROUND: Chylothorax is a rare but serious postoperative condition with a high rate of morbidity and may lead to the mortality of children undergoing congenital heart disease (CHD) surgery. This study evaluated the specific surgical procedures associated with the higher risk of postoperative chylothorax. METHODS: We assessed 435 cases undergoing CHD surgery between April 2003 and May 2006. We detected postoperative chylothorax in 6 patients. The diagnosis of chylothorax was established based on the presence of an odorless fluid with the characteristic milky appearance of the fluid (except when the patients were fasting in the immediate postoperative period), a triglyceride level greater than 110 mg/dL or between 50 and 110 mg/dL with a pleural fluid white cell count greater than 1000, and more than 80% lymphocytes on differential when the pleural fluid was not chylous. RESULTS: Over a 37-month period, 435 (mean age = 51.6 months; 232 males) patients underwent various types of surgical procedures for CHD; 6 patients developed chylothorax after the Fontan operation; one patient died due to severe chylothorax; 3 patients were managed by nutritional modifications, diuretics, and thoracocentesis; and 2 patients required thoracic duct ligation. The Fisher exact test analysis showed a significant association between the Fontan operation and postoperative chylothorax (p value < 0.0001). CONCLUSION: Our study showed a significant association between the Fontan surgery and chylothorax.