Background: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. Methods: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. Results: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients.Conclusions: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Cardiac 3D printing is mainly performed from magnetic resonance imaging (MRI) and computed tomography (CT) 3D datasets, though anatomic detail of atrioventricular (AV) valves may be limited. 3D echo provides excellent visualization of AV valves. Thus, we tested the feasibility and accuracy of 3D printing from 3D echo in this pilot series of subjects with congenital heart disease (CHD), with a focus on valve anatomy. Five subjects with CHD were identified. 3D echo data were converted to 3D printable files and printed in collaboration with 3D Systems Healthcare (Golden, Colorado). A novel technique for valve modeling was utilized using commercially available software. Two readers (KM, SA) independently measured valve structures from 3D models and compared to source echo images. 3D printing was feasible for all cases. Table 1 shows measurements comparing 2D echo to 3D models. Bland Altman analysis showed close agreement and no significant bias between 2D and digital 3D models (mean difference 0.0, 95% CI 1.1 to − 1.1) or 2D vs printed 3D models, though with wider limits of agreement (mean difference − 0.3, 95% CI 1.9 to − 2.6). Accuracy of 3D models compared to 2D was within < 0.5 mm. This pilot study shows 3D echo datasets can be used to reliably print AV and semilunar valve structures in CHD. The 3D models are highly accurate compared to the source echo images. This is a novel and value-added technique that adds incremental information on cardiac anatomy over current methods.

We report a pediatric patient with nonatherosclerotic chronic total occlusion (CTO) of the left main coronary artery (LMCA) leading to complete LMCA atresia which was successfully recanalized via retrograde techniques through a previous internal mammary bypass graft. After the CTO was treated, the artery was found to be anomalous off the right cusp with an intramural coarse and slit-like orifice. The patient's ischemic symptoms resolved after Percutaneous Coronary Intervention (PCI), and she has continued to do well.

Identification and treatment of hypertension should be an important focus of physicians caring for children. Ultimately, a link between hypertension in children and the risk of cardiovascular disease will be established. Further long-term studies are likely to show that morbidity and mortality will be decreased by the institution of treatment of hypertension in children. Additional risk factors such as obesity and lipid disorders should be sought and targeted for treatment as well. Lifestyle modifications are advised for all patients and can be tried solely for those with blood pressures between the 95th and 99th percentiles. Drug therapy is indicated in children with blood pressures greater than the 99th percentile, secondary hypertension, coexisting diabetes, left ventricular hypertrophy, or those who fail a trial of nonpharmacologic treatment. Children with white coat hypertension should not be treated with drugs. Children with renal artery stenosis and drug-refractory hypertension should be considered for percutaneous angioplasty or surgery depending on the anatomy of the lesion and operator experience. Children requiring multiple drug classes for control of blood pressure and older adolescents on one drug with renal artery lesions amenable to a percutaneous procedure may elect intervention in an attempt to reduce or eliminate drug therapy. Infants and children with hypertension due to native coarctation of the aorta should undergo surgical repair. Older children and adolescents with native coarctation should have surgical repair or percutaneous angioplasty/stenting. Hypertension secondary to recurrent coarctation is usually treated with a percutaneous intervention.

Antibiotics are known to alter the anticoagulation induced by warfarin in adults, but little is known about this interaction in children. In a retrospective review of patients under the age of 21 years, we found that antibiotic therapy (89 courses of antibiotics in 23 patients) was associated with an increase in the mean international normalized ratio (INR) from 2.7 to 3.6. The change in INR correlated inversely with patient age. These data suggest that more intensive monitoring of the INR after starting antibiotics may help to mitigate excessive anticoagulation in children receiving warfarin.

Baffle‐related complications following atrial switch procedures for transposition are relatively common. Transcatheter treatment of baffle stenosis has an established role as a therapeutic modality. However, transcatheter device closure of atrial baffles leaks has rarely been reported. We report four patients who underwent device closure of baffle leaks using the Amplatzer septal occluder following atrial switch procedures in order to demonstrate the safety and utility of this method of treatment and to establish its role as a suitable alternative to surgical closure. Catheter Cardiovasc Interv 2004;61:259–263. © 2004 Wiley‐Liss, Inc.

Purpose: Direct anastamosis of the pulmonary veins to the left atrium in living-donor lung transplantation (LDLT) may be more susceptible to torque or narrowing at suture lines than the cuff anastomosis of cadaveric lung transplantation (CLT). Perioperative TEE evaluation of these anastomotic sites is an important adjunct in the management of these patients.

Objective: Adult ventricular myocytes express two gap junction channel proteins: connexin43 (Cx43) and connexin45 (Cx45). Cx43-deficient mice exhibit slow ventricular epicardial conduction, suggesting that Cx43 plays an important role in intercellular coupling in the ventricle. Cx45 is much less abundant than Cx43 in working ventricular myocytes. Its role in ventricular conduction has not been defined, nor is it known whether expression or distribution of Cx45 is altered in Cx43-deficient mice. The present study was undertaken to determine (1) whether expression of Cx45 is upregulated and (2) whether gap junction structure and distribution are altered in Cx43-deficient mice. Methods: Ventricular tissue from neonatal Cx43(+/+), Cx43(+/-) and Cx43(-/-) and adult Cx43(+/+) and Cx43(+/-) mice was analyzed by immunoblotting and confocal immunofluorescence microscopy. Results: Total Cx45 protein abundance measured by immunoblotting was not different in Cx43-deficient or null hearts compared to wild-type control hearts. However, the amount and distribution of Cx45 immunoreactive signal measured by quantitative confocal analysis were markedly reduced in both Cx43(+/-) and Cx43(-/-) hearts. Conclusion: Although the total content of Cx45 is not upregulated in Cx43-deficient hearts, the localization of Cx45 to cardiac gap junctions depends on the expression level of Cx43 and is dramatically altered in mice that express no Cc43. (C) 2002 Elsevier Science BY All rights reserved.

OBJECTIVES:The purpose of this study was to prospectively characterize the reduction in right atrial (RA) area and right ventricular (RV) volume after transcatheter closure of atrial septal defect (ASD) and to investigate factors that may predict magnitude of resolution in right heart enlargement.BACKGROUND:Secundum ASD can cause volume overload of the right side of the heart with the potential for development of late complications. Little is known about reduction in right heart size after closure of ASD.METHODS:Transthoracic echocardiography was performed in 38 patients undergoing transcatheter closure of ASD. The RA area and RV volume were measured prior (n = 38), within 24 hours (n = 37), at 3 to 6 months (n = 24), at 12 months (n = 20) and at 24 months (n = 10) after closure of ASD. Change over time within the study group was assessed and the study group was compared to a control group of 19 patients with structurally normal hearts.RESULTS:Indexed RA area decreased from baseline to 3- to 6-month follow-up (p = 0.004) as did indexed RV volume (p < 0.0001). Indexed RV volume was similar to that in the control group at 24 months (p = 0.3); however, indexed RA area remained greater than in the control group (p = 0.006). Decrease in indexed RA area over the first 12 months of follow-up was related to young age at time of closure by regression analysis (r = 0.55, p = 0.013).CONCLUSION:Closure of secundum ASD results in decreased indexed RV volume comparable to that in control subjects at 24 months following closure. Indexed RA area remains increased compared to that in control subjects but does decrease over time. Decrease in RA area is inversely proportional to age at time of ASD closure. Long-term follow-up is required to evaluate the clinical impact of persistently increased RA size.

Na + Channel Activity in C×43‐Defident Myocytes. Introduction : Dynamic interplay between active and passive electrical properties of cardiac myocytes is based on interrelationships between various channels responsible for depolarizing and repolarizing ionic currents and intercellular conductances. Mice with targeted disruption of the connexin43 (C×43) gene have hearts completely devoid of C×43, the principal gap Junctional protein expressed in mammalian hearts. Methods and Results : To determine whether cardiac myocytes that develop in an abnormal environment of reduced intercellular coupling have altered active membrane properties, we studied whole cell action potentials, Na + channel currents, and Na + channel expression and distribution via immunoblotting and confocal immunofluorescence in neonatal ventricular myocytes isolated from C×43 wild‐type, heterozygous, and homozygous null hearts. Action potential morphology, peak Na + current, activation and inactivation kinetics, and Na + channel protein expression and distribution were not different among myocytes isolated from wild‐type, heterozygous, or null hearts. Active membrane properties and Na+ channel activity were completely normal in C×43‐deficient myocytes isolated from hearts that have been shown to exhibit markedly reduced C×43 expression, gap junction number, and epicardial conduction delay. Conclusion : Despite a genetic inability to produce C×43 and a developmental history that culminates in marked gross cardiac morphologic abnormalities, premature death, and myocardial inexcitability ex vivo, cardiac Na + channel distribution and function appear to he normal in C×43 null hearts. Although intimate structural and functional interrelationships have been described between ion channels and gap junction channels, expression and function of Na + channels is not affected by the absence of C×43.

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.

We investigated the prevalence and potential predictors of Doppler echocardiographic evidence of diastolic function in untreated hypertensive children. Doppler and M-mode echocardiographic values from 42 children (mean age 13, range 5-17 years) from a pediatric hypertension clinic were retrospectively reviewed and compared to data from 39 age and gender matched normotensive children in a control group. Compared to the participants in the control group, hypertensive patients had increased mean body mass index (29 v 19 kg/M2, P < .0001), peak mitral A velocity (57 v 42 cm/sec, P < .0001), isovolumic relaxation time (65 v 42 msec, P < .0001, resting heart rate (90 v 74 bpm, P < .0001), mitral E deceleration time (150 v 137 msec, P = .006), indexed left ventricular mass index (32 v 26 g/M2.7, P < .0001), relative left ventricular wall thickness (0.32 v 0.29, P = .02), and decreased ratio of peak mitral E velocity/peak mitral A velocity (1.7 v 2.1, P = .0001). Mean age, height, mitral E velocity, mitral A deceleration time, fractional shortening, and indexed left ventricular diastolic dimension were similar in patients and control group children. In the hypertensive patients, multivariate analysis demonstrated that heart rate (P = .0008) and systolic blood pressure (P = .03) were significant predictors of peak A velocity. In addition, heart rate (P = .0003), body mass index (P = .04), and indexed left ventricular diastolic dimension (P = .04) predicted the ratio of peak E/peak A velocity. None of the measures of diastolic function correlated with left ventricular mass index or relative wall thickness. Furthermore, none of the analyzed variables predicted isovolumic relaxation time or mitral E deceleration time. We conclude that untreated hypertensive children have Doppler indices suggestive of impaired left ventricular relaxation. Resting heart rate was the strongest predictor of abnormal diastolic indices.

To characterize the role of the gap junction protein connexin43 (Cx43) in ventricular conduction, we studied hearts of mice with targeted deletion of the Cx43 gene. Mice homozygous for the Cx43 null mutation (Cx43 -/-) die shortly after birth. Attempts to record electrical activity in neonatal Cx43 -/- hearts (n = 5) were unsuccessful. Ventricular epicardial conduction of paced beats, however, was 30% slower in heterozygous (Cx43 -/+) neonatal hearts (0.14+/-0.04 m/s, n = 27) than in wild-type (Cx43 +/+) hearts (0.20+/-0.07 m/s, n = 32; P < 0.001). This phenotype was even more severe in adult mice; ventricular epicardial conduction was 44% slower in 6-9 mo-old Cx43 -/+ hearts (0.18+/-0.03 m/s, n = 5) than in wild-type hearts (0.32+/-0.07 m/s, n = 7, P < 0.001). Electrocardiograms revealed significant prolongation of the QRS complex in adult Cx43 -/+ mice (13.4+/-1.8 ms, n = 13) compared with Cx43 +/+ mice (11.5+/-1.4 ms, n = 12, P < 0.01). Whole-cell recordings of action potential parameters in cultured disaggregated neonatal ventricular myocytes from Cx43 -/+ and +/+ hearts showed no differences. Thus, reduction in the abundance of a major cardiac gap junction protein through targeted deletion of a Cx43 allele directly leads to slowed ventricular conduction.

Refinements in cytogenetic techniques have promoted progress in understanding the role that chromosome abnormalities play in the cause of congenital heart disease. To determine if mutations at specific loci cause congenital heart disease, irrespective of the presence of other defects, and to estimate the prevalence of chromosome abnormalities in selected conotruncal cardiac defects, we reviewed retrospectively cytogenetic and clinical databases at St. Louis Children's Hospital. Patients with known 7q11.23 deletion (Williams syndrome), Ullrich-Turner syndrome (UTS), and most autosomal trisomies were excluded from this analysis. Two groups of patients were studied. Over a 6.5-year period, 57 patients with chromosomal abnormalities and congenital heart disease were identified. Of these, 37 had 22q11 deletions; 5 had abnormalities of 8p; and 15 had several other chromosome abnormalities. The prevalence of chromosome abnormalities in selected conotruncal or aortic arch defects was estimated by analysis of a subgroup of patients from a recent 22-month period. Chromosome abnormalities were present in 12% of patients with tetralogy of Fallot, 26% in tetralogy of Fallot/pulmonary atresia, 44% in interrupted aortic arch, 12% in truncus arteriosus, 5% in double outlet right ventricle, and 60% in absent pulmonary valve. We conclude that chromosome analysis should be considered in patients with certain cardiac defects. Specifically, fluorescent in situ hybridization (FISH) analysis of 22q11 is indicated in patients with conotruncal defects or interrupted aortic arch. High resolution analysis should include careful evaluation of the 8p region in patients with either conotruncal or endocardial cushion defects.

The major goals of this study were to define the relationships between intrapulmonary and systemic inflammatory responses in animals with gram-negative pneumonia. We treated rabbits with intrapulmonary Escherichia coli (1 x 10(7) to 1 x 10(10) cfu/ml), and then measured physiologic, cellular, and molecular events in the lungs and systemic circulation for 24 h. The treatment protocols resulted in groups of animals that mimicked the stages of the septic inflammatory response in humans. Animals treated with low inocula had systemic changes consistent with systemic inflammatory response syndrome and cleared the bacteria and inflammatory products from the lungs. Animals treated with high inocula failed to clear bacteria from the lungs, had severe intrapulmonary inflammatory responses, and developed septic shock. Intrapulmonary leukocyte recruitment was directly related to the size of the bacterial inoculum, but lung protein accumulation was not. Tumor neurosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and GRO were detectable in lung lavage fluid at 4 h and declined by 24 h in animals that cleared intrapulmonary E. coli. In contrast, lavage TNF-alpha, IL-8, and GRO increased over 24 h in animals that failed to clear intrapulmonary bacteria. MCP-1 increased between 4 h and 24 h in the lungs of all of the animals as the histologic response evolved from neutrophilic to mononuclear cell predominance. Thus, the intensity of systemic inflammatory and physiologic responses to intrapulmonary gram-negative infection depends on the inoculum size and whether the bacteria are cleared from or proliferate in the lungs. The results provide experimental support for the recently proposed classification of septic responses in humans.