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The purpose of this study was to describe the long-term outcome of infants with hypoplastic left heart syndrome (HLHS) who underwent placement of internal pulmonary artery bands as part of a transcatheter palliation procedure followed by primary heart transplantation. Transcatheter palliation included stenting of the ductus arteriosus, decompression of the left atrium by atrial septostomy, and internal pulmonary artery band placement. Cardiac hemodynamics, pulmonary artery architecture, and pulmonary artery growth since transplantation are described. Nine infants with HLHS had internal pulmonary artery bands placed and underwent successful heart transplant. No infant required reconstruction of the pulmonary arteries at the time of transplant. At 1 year after transplant, all of the recipients had normal mean pulmonary artery pressure, pulmonary vascular resistance, and transpulmonary gradient. Pulmonary angiography performed at 1 year after transplant demonstrated no distortion of pulmonary artery anatomy with significant interval growth of the branch pulmonary arteries. There was 100% survival to hospital discharge after transplant in this cohort of infants. Transcatheter placement of internal pulmonary artery bands for HLHS offers protection of the pulmonary vascular bed while preserving pulmonary artery architecture and growth with good long-term outcome.

Objectives: The objectives of this study are to report the spectrum of cardiac lesions in pediatric patients post-orthotopic heart transplantation (OHT), the characteristics of patients who develop these lesions, and the feasibility of transcatheter intervention in treating these lesions., Background: Indications for OHT in the pediatric population range from cardiomyopathy to complex congenital heart defects with and without prior palliation. These patients may have residual vascular access and great vessel abnormalities., Methods: Data was collected through retrospective review of all OHT patients at our institution from 1988 to 2005., Results: During the study period, 276 heart transplants were performed. Forty-seven patients, age 1.6 [0.1-26] years with a weight of 9.5 [3.5-96.0] kilograms, underwent 69 procedures. Patients with original diagnoses of hypoplastic left heart syndrome and failed palliations required intervention most frequently. Sixteen patients, all with a history of left sided disease, developed aortic arch obstruction. Fifteen were successfully treated with balloon angioplasty while one has recurrent supravalve aortic obstruction. Fourteen patients had superior vena cava obstruction treated with balloon angioplasty and/or stent placement. Twelve patients required no further intervention and two required further stent placement. Ilio-femoral vein occlusion was treated with balloon angioplasty alone in 4 patients and stent placement in 10 patients to achieve vessel patency. Other procedures included treatment of branch pulmonary artery and pulmonary vein stenosis., Conclusion: Anastomotic aortic arch and venous obstructive lesions should be sought following pediatric OHT as they occur in almost 20% of patients and can be successfully addressed using interventional techniques., ((c) 2008 Wiley-Liss, Inc.)

In three infants awaiting orthotopic cardiac transplantation, transplantation was successfully performed with the use of organs from donors who had died from cardiocirculatory causes. The three recipients had blood group O and were in the highest-risk waiting-list category. The mean age of donors was 3.7 days, and the mean time to death after withdrawal from life support was 18.3 minutes. The 6-month survival rate was 100% for the 3 transplant recipients and 84% for 17 control infants who received transplants procured through standard organ donation. The mean number of rejection episodes among the three infants during the first 6 months after surgery was 0.3 per patient, as compared with 0.4 per patient among the controls. Echocardiographic measures of ventricular size and function at 6 months were similar among the three infants and the controls (left ventricular shortening fraction, 43.6% and 44.9%, respectively; P=0.73). No late deaths (within 3.5 years) have occurred in the three infants, and they have had functional and immunologic outcomes similar to those of controls. Mortality while awaiting a transplant is an order of magnitude higher in infants than in adults, and donors who died from cardiocirculatory causes offer an opportunity to decrease this waiting-list mortality., (2008 Massachusetts Medical Society)

Context: Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents., Objective: To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction., Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months)., Interventions: Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not., Main Outcome Measures: The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels., Results: There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend)., Conclusions: These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology., Trial Registration: clinicaltrials.gov Identifier: NCT00052026.

Background: Control of distal pulmonary artery (PA) pressure and flow is a critical step in palliating infants with complex congential heart disease. Surgical procedures to protect or isolate the pulmonary circulation carry significant risk and can be unpredictable. Interventional control of pulmonary pressure/flow with an intravascular device (band) could reduce risk and improve regulation of pulmonary flow., Methods: Internal pulmonary bands were created from woven nitinol to create an internal orifice estimated to reduce distal pulmonary arterial pressure by 50%. Two designs were tested, a single eccentric lumen and two symmetrical lumens. The devices were approximately 7-mm long and the external diameter varied to suit the pulmonary arterial lumen size. A total of 15 devices were implanted in seven lambs with a stented ductus arteriosus to create high pulmonary pressure/flow. Four lambs were followed with devices and stent in place for a mean of 37 +/- 13 days., Results: Fourteen of 15 devices were successfully implanted. One was acutely removed since the size was too large. Both device designs created greater than a 50% reduction in distal pulmonary pressure. Main PA pressure was 70/38, mean 50 +/- 13 mm Hg, and distal PA pressure 25/16, mean 20 +/- 7 mm Hg (P < 0.05). Angiography demonstrated protection of the internal banded pulmonary segments from overcirculation. Late follow-up showed that the device lumen(s) remained patent. Histology showed the vessel media to be intact but there was intimal proliferation where the device approximated the wall. There were no thrombotic emboli detected., Conclusion: Percutaneous internal banding of the pulmonary arteries was feasible and successful in lambs with high pulmonary flow/pressure analogous to infants with complex congenital heart disease., ((c) 2007 Wiley-Liss, Inc.)

Thymopoietin or TMPO (indicated by its alternative gene symbol, LAP2, in this work) has been proposed as a candidate disease gene for dilated cardiomyopathy (DCM), since a LAP2 product associates with nucleoplasmic lamins A/C, which are encoded by the DCM gene LMNA. We developed a study to screen for genetic mutations in LAP2 in a large collection of DCM patients and families. A total of 113 subjects from 88 families (56 with familial DCM (FDC) and 32 with sporadic DCM) were screened for LAP2 mutations using denaturing high-performance liquid chromatography and sequence analysis. We found a single putative mutation affecting the LAP2alpha isoform in one FDC pedigree. The mutation predicts an Arg690Cys substitution (c.2068C>T; p.R690C) located in the C-terminal domain of the LAP2alpha protein, a region that is known to interact with lamin A/C. RT-PCR, Western blot analyses, and immunolocalization revealed low-level LAP2alpha expression in adult cardiac muscle, and localization to a subset of nuclei. Mutated Arg690Cys LAP2alpha expressed in HeLa cells localized to the nucleoplasm like wild-type LAP2alpha, with no effect on peripheral and nucleoplasmic lamin A distribution. However, the in vitro interaction of mutated LAP2alpha with the pre-lamin A C-terminus was significantly compromised compared to the wild-type protein. LAP2 mutations may represent a rare cause of DCM. The Arg690Cys mutation altered the observed LAP2alpha interaction with A-type lamins. Our finding implicates a novel nuclear lamina-associated protein in the pathogenesis of genetic forms of dilated cardiomyopathy., (Copyright 2005 Wiley-Liss, Inc.)

Background: The study analyzed the effect of atrial septal defect (ASD) device closure on regional wall motion in the right (RV) and left ventricles (LV) using color tissue Doppler imaging (TDI). Atrial septal defect closure results in acute volume unloading of the RV. For unknown reasons, some patients develop acute left-sided heart failure postintervention., Methods: Color TDI was performed in 39 pediatric ASD and 75 age-matched controls. Regional wall motion in 5 LV and 1 RV segment were analyzed before, immediately after, and 24 hours after interventional ASD closure. Off-line postprocessing of echocardiographic data was used to determine myocardial velocities and acceleration during isovolumic contraction (IVA). Isovolumic contraction acceleration is the slope of the upstroke of the isovolumic contraction wave (IVA = peak velocity/acceleration time)., Results: At baseline, patients with ASD had significantly higher RV systolic velocities than controls. Isovolumic contraction acceleration was similar in patients with ASD and controls. In the catheterization laboratory postintervention, conventional function parameters remained stable but systolic myocardial velocities decreased significantly in all segments. Diastolic velocities fell in LV segments but not in the RV. In contrast to velocities, IVA was stable during ASD device closure. On follow-up at 24 hours, myocardial velocities had normalized., Conclusions: Device closure of ASD results to an acute transient decrease of regional myocardial velocities in the LV and RV, whereas the load-insensitive marker isovolumic acceleration remained stable. Therefore, the velocity changes may represent a response to altered left and right ventricular loading conditions. Color TDI is a sensitive tool to analyze ventricular mechanics.

Background: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM., Methods and Results: A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for alphaMyHC gene (MYH6) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure., Conclusions: This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.

The single largest cause of late graft loss in pediatric cardiac transplantation is transplant coronary artery vasculopathy (CAV). The mechanism of CAV remains unknown; it appears to have both immune and non-immune causes. The final common pathway of these mechanisms is endothelial activation, a prothrombotic environment, and endothelial damage with subsequent diffuse intimal proliferation. The disease process has largely been thought to be progressive and unresponsive to treatment. Re-transplantation has been advocated as the only definitive treatment. The appropriate management is largely unknown; intervention or surgical management has had limited utility, while medical management appears to have the most promise. Improvement in outcome can be achieved by optimizing non-immune factors and aggressive management of the immune mechanisms. Long-term survival of transplant patients after diagnosis with CAV is now being reported.

Background: Carvedilol is a medication with both beta-receptor and alpha-receptor blocking properties that has been approved for the treatment of heart failure in adults. Little is known about its safety, efficacy, pharmacokinetics, and dosing profile in children., Methods: The primary objective of this study is to evaluate the efficacy of carvedilol administered twice daily for 8 months in terms of its effect compared with placebo on a composite measure of clinical outcomes in children with symptomatic systemic ventricular systolic dysfunction and heart failure. The secondary objectives are to determine the effect of carvedilol on individual components of a composite of clinical outcomes (hospitalizations for worsening heart failure, all-cause mortality and cardiovascular hospitalizations, all cause mortality, heart failure symptoms, and patient and physician global assessment); determine the effect of carvedilol on echocardiographic indices of ventricular function and remodeling; characterize the pharmacokinetics of carvedilol in pediatric patients with heart failure; characterize the effects carvedilol on neurohormonal systems; and provide data for the selection of an optimal titration schedule and daily dose of carvedilol in children with heart failure. This study will enroll 150 children between birth and 17 years of age with chronic symptomatic heart failure caused by systemic ventricular systolic dysfunction., Conclusion: This study will determine whether carvedilol improves symptoms in children with heart failure as a result of systemic ventricular systolic dysfunction. The study also will provide information on echocardiographic changes of ventricular performance and neurohormonal levels in children with heart failure before and after treatment with carvedilol, in addition to pharmacokinetics of carvedilol in children.