Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.

Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.

Congenital heart disease caused by mutations in the transcription factor NKX2-5.

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.

Comparison of four Doppler echocardiographic methods for calculating pulmonary-to-systemic shunt flow ratios in patients with ventricular septal defect.

Several methods currently exist for quantifying pulmonary (Qp) and systemic (Qs) shunt flow using Doppler echocardiography, although none is widely utilized. In this study, 39 patients (age 2 months to 12 years, mean 2.1 years) underwent an echocardiographic examination within 1 month of Qp:Qs shunt flow determination by oximetry at catheterization. Qp:Qs was determined by 4 methods that utilized: (1) velocity time integrals and luminal areas to estimate volume flow of the pulmonary artery and aorta; (2) the square of the ratios of pulmonary artery to aorta, multiplied by the ratio of pulmonary to aortic peak flow velocities; (3) inclusion of mitral and tricuspid valve volume flow to pulmonary and aortic volume flow; and (4) ventricular septal defect (VSD) diameter and velocity time integral to calculate left-to-right shunt, which, when added to aortic volume flow (Qs), can be used to estimate Qp. Each of the first 3 methods was statistically correlated to the oximetry Qp:Qs, with r values ranging from 0.54 to 0.66 (p < 0.001). However, the fourth method, based on direct computation of flow across the VSD, had the best correlation to catheterization data (r = 0.82), and further improved when 7 patients with a large VSD (> 9 mm/m2), all of whom had bidirectional shunting, were removed (r = 0.90). Thus, we concluded that this latter method demonstrated the best correlation to catheterization-derived shunt flow data, and because this method is somewhat less labor-intensive than the others, should provide clinically useful data well suited for serial evaluation in infants and children with VSD.

Aortic regurgitation at diagnosis of HLA-B27 associated spondyloarthropathy.

A 14-year-old boy with a 9 month history of rheumatic symptoms was found to have hemodynamically significant aortic regurgitation in association with an HLA-B27 associated spondyloarthropathy (SpA). Valvular incompetence due to aortitis can occur early in the clinical course of pediatric patients with SpA, and careful cardiac monitoring is warranted.

Effect of patent ductus arteriosus on Doppler-derived right ventricular systolic time intervals.

Right ventricular systolic time intervals (RVSTI) and noninvasive Doppler-derived pulmonary blood flow were measured before and after surgical ductus ligation in 18 otherwise healthy infants and children who were older than 3 months of age. Right ventricular preejection period (PEP) and the ratio of preejection period and right ventricular ejection time (PEP/RVET), both corrected or uncorrected for heart rate, decreased significantly following surgery (PEP 71 +/- 14 vs. 50 +/- 13, p < 0.001 and PEP/RVET 0.29 +/- 0.06 vs. 0.21 +/- 0.05, p < 0.001). The volume of pulmonary blood flow correlated with PEP/RVET (r = 0.48, p = 0.003). The magnitude of the change in pulmonary blood flow correlated with the change in PEP/RVET (r divided by 0.56, p = 0.016). The velocity of circumferential fiber shortening (VCFc) increased after surgery, but not significantly. We speculate that patent ductus arteriosus has a similar effect on right ventricular performance when other congenital heart defects are present.

Academic physicians' opinions on preliminary reporting of echocardiographic data.

Preliminary reporting of echocardiographic data by cardiac sonographers has become a key issue in the echocardiography community. A survey on this issue was sent to 248 academic physicians and 89 (35.8%) were returned. In response to a question in the survey, 76 physicians stated that they had at least a limited amount of knowledge in echocardiography. For the group, 62% wanted a written or verbal preliminary report and 52% concluded that this report should be a part of the cardiac sonographer's position. If cardiac abnormalities are suspected, 65% wanted the results before the cardiologist reviewed the study, but only 42% of the physicians wanted a diagnostic versus a descriptive type of report. About 49% stated that if necessary they would attempt to influence the cardiac sonographer to give them a preliminary report, whereas 67% of the physicians would possibly use this information to medically manage the patient. Fifty percent believed that it was legal for a cardiac sonographer to give a preliminary report. Another 70% said that the cardiac sonographer would NOT be "practicing medicine without a license" and 66% concluded that they would NOT be "aiding and abetting the unauthorized practice of medicine" if given this information. These data have important potential ramifications for both cardiac sonographers as well as for the practice of cardiology regarding the issue of preliminary echocardiographic reports.