Survival in Children With Down Syndrome Undergoing Single-Ventricle Palliation.

BACKGROUND: We describe survival in patients with Down syndrome (DS) with single-ventricle anatomy and palliation and characterize risk factors associated with mortality. METHODS: All patients with DS and single-ventricle anatomy documented in the electronic medical record at our institution from January 1, 1992, to May 1, 2014, were compared with patients with unbalanced atrioventricular septal defects and single-ventricle anatomy, without DS or heterotaxy, during the same period. Survival analysis was performed to evaluate factors associated with mortality, including the presence of DS. RESULTS: There were 28 patients with DS and 30 patients without DS. One-year survival with DS was 75% (95% CI: 55% to 87%); 5-year survival was 61% (95% CI: 40% to 76%). All DS deaths except one occurred before 2 years of age. One-year non-DS survival was 93% (95% CI: 76% to 98%); 5-year survival was 85% (95% CI: 64% to 94%). Factors associated with death by univariable analysis included DS (p = 0.04), pulmonary vascular resistance (PVR) of at least 3 Wood units × meter(2) (WUm(2)) in the first year of life (p = 0.03), and moderate-to-severe atrioventricular valve regurgitation (p = 0.1). In combined analysis, when accounting for PVR of at least 3 WUm(2) (hazard ratio [HR] 9.8, 95% CI: 1.1 to 83.5, p = 0.04), DS was not associated with increased mortality (HR 1.5, 95% CI: 0.3 to 7.8, p = 0.66). No patient with DS with PVR less than 3 WUm(2) died. CONCLUSIONS: Children with DS and single-ventricle anatomy have excellent survival when PVR is less than 3 WUm(2) in the first year of life, with minimal mortality beyond 2 years of age. When accounting for PVR, DS alone is not associated with increased mortality in patients with single-ventricle anatomy.

Arrhythmias in children with ventricular assist devices.

BACKGROUND: Children with decompensated heart failure are at high risk for arrhythmias, and ventricular assist device placement is becoming a more common treatment strategy. The impact of ventricular assist devices on arrhythmias and how arrhythmias affect the clinical course of this population are not well described. METHODS AND RESULTS: A single-centre retrospective analysis of children receiving a ventricular assist device between 1998 and 2011 was performed. In all, 45 patients received 56 ventricular assist devices. The median age at initial placement was 13 years (interquartile range 6-15). The median duration of support was 10 days (range 2-260). The aetiology of heart failure included cardiomyopathy, transplant rejection, myocarditis, and congenital heart disease. In all, 32 patients (71%) had an arrhythmia; 19 patients (42%) had an arrhythmia before ventricular assist device and eight patients (18%) developed new arrhythmias on ventricular assist device. Ventricular tachycardia was most common (25/32, 78%). There was no correlation between arrhythmia and risk of death or transplantation (p=0.14). Of the 15 patients who weaned from ventricular assist device, post-ventricular assist device arrhythmias occurred in nine (60%), with five (33%) having their first arrhythmia after weaning. Patients with ventricular dysfunction after ventricular assist device were more likely to have arrhythmias (p<0.02). CONCLUSIONS: Arrhythmias, especially ventricular, are common in children requiring ventricular assist device. They frequently persist for those able to wean from ventricular assist device.

ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle.

ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.

Angiotensin-converting enzyme inhibitor nephrotoxicity in neonates with cardiac disease.

Angiotensin-converting enzyme inhibitors (ACEi) are commonly used for pediatric cardiology patients. However, studies examining their safety for neonates with cardiac disease are scarce. The current study aimed to test the hypothesis that ACEi-mediated nephrotoxicity occurs in neonates and may be underappreciated in this population. A retrospective review of 243 neonates with cardiac disease between 2007 and 2010 was performed. Demographic data, weight, length, captopril and enalapril dosing, serum [K⁺], serum creatinine, and concomitant medications during ACEi therapy were recorded and analyzed. Body surface area (BSA), creatinine clearance (CrCl), and change in [K⁺] were calculated. The age range of neonates at ACEi initiation was 15.9-18.1 days. The inclusion criteria was met by 206 neonates: 168 term (82%) and 38 preterm (18%) newborns. Of these neonates, 42% were female, and all the patients had a BSA smaller than 0.33 m² (a group known to have relative renal insufficiency). The mean dose of enalapril was 0.08 ± 0.007 mg/kg for the preterm neonates and 0.08 ± 0.003 mg/kg for the term neonates. The mean dose of captopril was 0.07 ± 0.009 mg/kg for the preterm neonates and 0.13 ± 0.019 mg/kg for the term neonates. A significant decrease in CrCl occurred for both the preterm (p < 0.01) and term (p < 0.001) neonates while they were receiving ACEi. However, the two groups did not differ significantly (p = 0.183). Nearly 42% of all the patients showed renal risk, with approximately 30% demonstrating renal failure by modified pRIFLE (pediatric risk, injury, failure, loss, and end-stage renal disease) criteria. Despite the lack of significantly different CrCl, the premature neonates were more likely to experience ACEi-related renal failure by pRIFLE (55%) than their term counterparts (23%; p < 0.001). Despite its common use for term neonates with cardiac disease, ACEi should be used cautiously and only when indications are clear. These results also raise the question whether ACEi should be used at all for preterm neonates.

Pulmonary hypertension associated with congenital heart disease: a practical review for the pediatric cardiologist.

Pulmonary hypertension (PH) is a complex condition with a broad range of etiologies that result in a common outcome--elevated pulmonary arterial pressure. For the pediatric cardiologist, this entity provides a manifest demonstration of the interrelationship of cardiac and pulmonary physiology. A thoughtful approach must be applied to each patient with PH in order to achieve a thorough understanding of the nature of disease and to proceed with individualized therapy in an appropriate and timely manner. This article aims to provide a clinically relevant, practical review of current literature related to PH in patients with congenital heart disease, including the causes, diagnostic considerations, and an overview of management.

Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction.

BACKGROUND: Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. METHODS AND RESULTS: Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. CONCLUSIONS: ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5.

Limited utility of exercise stress tests in the evaluation of children with chest pain.

OBJECTIVES: The objective of this study was to assess the utility of the exercise stress test (EST) in pediatric patients without previously diagnosed heart disease who present with chest pain and to correlate EST results with echocardiographic findings. DESIGN: Retrospective chart review over a 14-month period. SETTING: Cardiology clinic at an academic children's hospital. PATIENTS: Two hundred three pediatric patients who presented to a pediatric cardiologist and had an EST for chest pain. OUTCOME MEASURES: Correlate EST results with echocardiographic findings and the patient's ultimate diagnosis. METHODS: Retrospective review of patients who presented to cardiology clinic for chest pain, analysis of medical records, EST, echocardiograms, and other downstream testing. RESULTS: Of 433 patients who presented to a pediatric cardiologist for chest pain, 203 (47%) had an EST performed. One hundred seventy-six (87%) patients did not have a prior diagnosis of congenital heart disease and made up our study population. Mean age was 13.2 ± 3 years. Of the patients who had an EST, 139 (79%) had chest pain with exercise. Echocardiography was performed in 124 (70%) of the patients who had an EST. Of patients undergoing echocardiography, 17/124 (14%) had abnormalities, but none of the abnormalities found were thought to contribute to the patients' chest pain. There were only four (2%) abnormal EST, and none were thought to be diagnostic for the patients' symptoms of chest pain. The most common diagnoses were musculoskeletal chest pain in 34 patients (19%) and reactive airway disease in 27 patients (15%). CONCLUSION: In children referred to pediatric cardiology clinic for chest pain, EST has a low yield in identifying cardiac abnormalities.