Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve.

Bicuspid Aortic Valve (BAV) is a highly heritable congenital heart defect. The low frequency of BAV (1% of general population) limits our ability to perform genome-wide association studies. We present the application of four a priori SNP selection techniques, reducing the multiple-testing penalty by restricting analysis to SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV probands and 830 control subjects. Two knowledge-based approaches, CANDID and STRING, were used to systematically identify BAV genes, and their SNPs, from the published literature, microarray expression studies and a genome scan. We additionally tested Functionally Interpolating SNPs (fitSNPs) present on the array; the fourth consisted of SNPs selected by Random Forests, a machine learning approach. These approaches reduced the multiple testing penalty by lowering the fraction of the genome probed to 0.19% of the total, while increasing the likelihood of studying SNPs within relevant BAV genes and pathways. Three loci were identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926x10(-06)) and a haplotype within the Endoglin gene (p-value of 5.881x10(-04)) were found to be strongly associated with BAV. The Random Forests approach identified a SNP on chromosome 3 in association with BAV (p-value 5.061x10(-06)). The results presented here support an important role for genetic variants in BAV and provide support for additional studies in well-powered cohorts. Further, these studies demonstrate that leveraging existing expression and genomic data in the context of GWAS studies can identify biologically relevant genes and pathways associated with a congenital heart defect.

Differential expression of neuronal fos protein after cold water drowning and controlled rewarming.

BACKGROUND: Cardiopulmonary bypass has often been applied to revive victims of cold water drowning. The success of resuscitative efforts in patients who have sustained severe hypothermia is largely determined by neurologic outcomes. Measurement of Fos, the protein product of the immediate-early gene c-fos, is a marker of cerebral injury. STUDY DESIGN: Twenty-eight infant lambs were sedated and ventilated. Group 1 lambs were immersed in a cold water bath for 2 hours (17.3 +/- 2.7 degrees C). Group 2 lambs were placed on normothermic cardiopulmonary bypass for 2 hours (37.7 degrees +/- 0.7 degrees C). Group 3 lambs were immersed in a cold water bath for 2 hours (17.6 degrees +/- 2.4 degrees C), and then rewarmed for a period of 2 hours on cardiopulmonary bypass (37.0 degrees +/- 0.6 degrees C). The lambs were euthanized and immunohistochemical analysis for neuronal Fos was performed. RESULTS: There was significant induction of Fos-labeled nuclear profiles (cells/1130 microm(2)) in group 3 in the hippocampal regions and dentate gyrus compared with groups 1 and 2 (p < 0.001). CONCLUSION: Isolated exposure to either hypothermia or cardiopulmonary bypass results in minimal expression of neuronal Fos; the significant induction of Fos in the group 3 animals may represent an ischemic-reperfusion phenomenon. Modifications of rewarming techniques that minimize Fos expression may improve neurologic outcomes in victims of cold water drowning.

Expanding the indications for pulmonary valve replacement after repair of tetralogy of fallot.

BACKGROUND: Insertion of a competent pulmonary valve has been advocated to reduce right ventricular volume overload associated with pulmonary regurgitation (PR) after repair of tetralogy of Fallot. However the indications, proper timing, and long-term benefits of restoring pulmonary valve function remain controversial. METHODS: Thirty-six patients (aged 15.2 +/- 9.2 years) underwent pulmonary valve implantation (31 homografts, 5 heterografts) 12.2 +/- 6.9 years after tetralogy repair. Additional surgical procedures included pulmonary artery augmentation (n = 14), closure of septal defects (n = 10), and cryoablation and endocardial resection of ventricular tachycardia (n = 2). RESULTS: All patients have had clinical improvement in their exercise capacity. Preoperative and postoperative bicycle ergometry tests in 6 patients demonstrated significant improvement in the percent of predicted peak workload (68.5% +/- 19.8% to 80.7% +/- 17.4%, p < 0.015). One midterm death occurred in a 38-year-old patient with a history of ventricular tachycardia who died suddenly 2 years after pulmonary valve insertion. Postoperative echocardiographic measurements were available in 34 patients at a mean follow-up of 5 years. There was a 30% reduction in right ventricular end-diastolic diameter indexed to body surface area after surgery (30.1 +/- 10.2 to 18.6 +/- 6.0 mm/m(2), p < 0.0001). Two patients required conduit replacements at 1 and 9 years postoperatively. CONCLUSIONS: Timely insertion of a competent pulmonary valve in children, adolescents, and young adults with significant PR after tetralogy of Fallot repair results in subjective and objective improvement in exercise capacity and is associated with reduction in right ventricle size.