atrial-natriuretic-factor and Heart-Septal-Defects--Ventricular

Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient's pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband's close relatives also had pulmonary stenosis (PS), and the proband's son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5-two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5.

Topics: Adolescent; Alleles; Amino Acid Substitution; Atrial Natriuretic Factor; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Child; Child, Preschool; Codon; DNA Mutational Analysis; Female; GATA4 Transcription Factor; Genetic Association Studies; Heart Septal Defects, Ventricular; Homeobox Protein Nkx-2.5; Humans; Infant; Infant, Newborn; Male; Mutation; Pedigree; Promoter Regions, Genetic; Pulmonary Valve Stenosis; Transcription Factors; Transcriptional Activation; Young Adult

The basic helix-loop-helix transcriptional repressor Hairy-related transcription factor 2 (Hrt2) is expressed in ventricular, but not atrial, cardiomyocytes, and in endothelial and vascular smooth muscle cells. Mice homozygous for a null mutation of Hrt2 die perinatally from a spectrum of cardiac abnormalities, raising questions about the specific functions of this transcriptional regulator in individual cardiac cell lineages. Using a conditional Hrt2 null allele, we show that cardiomyocyte-specific deletion of Hrt2 in mice results in ectopic activation of atrial genes in ventricular myocardium with an associated impairment of cardiac contractility and a unique distortion in morphology of the right ventricular chamber. Consistent with the atrialization of ventricular gene expression in Hrt2 mutant mice, forced expression of Hrt2 in atrial cardiomyocytes is sufficient to repress atrial cardiac genes. These findings reveal a ventricular myocardial cell-autonomous function for Hrt2 in the suppression of atrial cell identity and the maintenance of postnatal cardiac function.

Topics: Animals; Atrial Natriuretic Factor; Basic Helix-Loop-Helix Transcription Factors; Female; Gene Expression Regulation; Heart; Heart Atria; Heart Septal Defects, Ventricular; Mice; Myocardial Contraction; Rats; Receptors, Notch; Repressor Proteins; Signal Transduction; T-Box Domain Proteins

There is little information available concerning plasma concentrations of B-type natriuretic peptide (BNP) in children with a ventricular septal defect. The aim of the present study was to determine hemodynamic factors that control plasma concentrations of BNP and the clinical implications of BNP compared with atrial natriuretic peptide (ANP) in children with ventricular septal defect.. Fifty-nine patients with ventricular septal defect (28 boys and 31 girls) without pulmonary vascular disease were enrolled. The patients' ages ranged from 3 months to 13 years (mean 3.1 years). Plasma BNP and ANP were determined by immunoradiometric assay. Hemodynamic variables derived from cardiac catheterization were analyzed in terms of correlation with BNP and ANP.. It was found that plasma BNP significantly positively correlated with ANP (ANP = 2.1 x BNP + 25 pg/mL; r = 0.81, P < 0.0001) and BNP never exceeded ANP in the present patient series. Plasma BNP as well as ANP significantly positively correlated with pulmonary to systemic flow ratio (r = 0.65 and r = 0.59, respectively) and mean pulmonary artery pressure (r = 0.72 and r = 0.68, respectively). In addition, plasma BNP of > or =20 pg/mL and ANP of > or =50 pg/mL identified children with mean pulmonary artery pressure of > or =20 mmHg with a sensitivity of 82% and 97%, respectively, and a specificity of 89% and 84%, respectively.. Plasma BNP and ANP reflect pressure and volume loads to the pulmonary artery and right ventricle and may help to identify children with ventricular septal defect complicated by pulmonary hypertension that demands early intervention.

Topics: Adolescent; Atrial Natriuretic Factor; Blood Pressure; Child; Child, Preschool; Female; Heart Failure; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Infant; Male; Natriuretic Peptide, Brain; Pulmonary Circulation; Vascular Resistance

The capacity to secrete human atrial natriuretic peptide (hANP) in response to atrial pacing and the resulting changes in diuresis and urinary electrolyte excretion were compared in children with and without a ventricular septal defect (VSD). The subjects examined were 9 children with a history of Kawasaki disease (as controls) and 11 patients with a VSD, including 5 patients with congestive heart failure (CHF). Their ages ranged from 6 to 40 months old. Atrial pacing resulted in a significant increase in the plasma hANP level from 40 +/- 19 to 140 +/- 37 pg/ml in the controls and from 757 +/- 762 to 1540 +/- 1160 pg/ml in the VSD patients. In control children, the urinary flow rate increased 2.3-fold, urinary sodium excretion increased 6.2-fold and urinary chloride excretion increased 7.6-fold, but these values increased only slightly in VSD patients, especially in those patients with CHF, in spite of the marked increase in their plasma hANP level. These results indicate that the capacity for hANP secretion was increased in VSD patients who had chronic volume overloading of the left atrium, but that their diuresis and urinary electrolyte excretion in response to hANP were attenuated.

Topics: Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Child, Preschool; Chlorides; Diuresis; Heart Atria; Heart Failure; Heart Septal Defects, Ventricular; Humans; Infant; Natriuresis; Potassium; Sodium

The plasma level of human alpha-atrial natriuretic peptide was measured in healthy children and patients, 1 month to 15 years of age, with congenital heart diseases. Significant increases were found in patients with a ventricular septal defect, tricuspid valve atresia, patent ductus arteriosus, and atrial septal defect but not in those with pulmonary valve stenosis or tetralogy of Fallot. The levels were significantly higher in children with ventricular septal defects (221 +/- 123 pg/mL) or patent ductus arteriosus (124 +/- 38 pg/mL) than in those with atrial septal defects (65 +/- 42 pg/mL) (P less than .01). The increased levels appeared to be correlated with enlargement of the left atrium (r = .85, P less than .01) but not with the right atrial size or the mean right atrial pressure. They were higher in younger than in older healthy infants, but this age difference did not affect the results. These findings indicate that human alpha-atrial natriuretic peptide is released into the circulation in response to chronic atrial expansion in patients with congenital heart disease and may have an important role in volume homeostasis.

Topics: Adolescent; Atrial Natriuretic Factor; Child; Child, Preschool; Ductus Arteriosus, Patent; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Infant; Male; Pulmonary Valve Stenosis; Tetralogy of Fallot; Tricuspid Valve

Plasma levels of human atrial natriuretic peptide were determined during different stages of a symptom-limited bicycle ergometer stress test. Eight healthy persons and three patients suffering from well-defined cardiac disorders were examined. Measurements of the peptide were performed before the exercise, at 75 watts, at maximal work load, and 10 and 30 min after ceasing the exercise. In healthy persons plasma levels of the peptide increased from preexercise levels of 4-41 ng/l to 16-59 ng/l at maximal work load, but remained in the normal range (10-70 ng/l). In contrast, in the cardiac patients, levels of the peptide were up to 8-fold higher at maximal physical exertion (154-270 ng/l) than at rest (34-86 ng/l). Within a recovery period of 30 min hormone concentrations returned almost to preexercise levels.

Topics: Aged; Atrial Natriuretic Factor; Female; Heart Aneurysm; Heart Failure; Heart Septal Defects, Ventricular; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Physical Exertion