Postnatal Outcome of Fetal Left Ventricular Hypertrabeculation/Noncompaction.

Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology. Prenatal diagnosis of LVHT can be established by fetal echocardiography. A review of 106 published cases showed that 46 cases with prenatally diagnosed LVHT were alive 0.5-120 months after birth. Since the course of cases with prenatally LVHT after publication is unknown, we aimed to collect follow-up-information. Information regarding vital status, cardiac and extracardiac morbidity was gathered by contacting the authors of the 46 cases. Fourteen of the 28 authors answered and gave information about 18 cases (six females, seven males, five gender-unknown, age 18 months to 10 years, mean follow-up 60 months). No differences were found between the 18 cases with follow-up and the 28 cases without follow-up regarding age, gender, cardiac or extracardiac comorbidities, and interventions. Three of the 18 cases had died subsequently from heart failure, osteosarcoma, and enterocolitis, respectively. Mutations or chromosomal abnormalities were found in six of the seven examined patients, extracardiac abnormalities in nine patients. Three patients received a pacemaker because of complete AV block, and two patients underwent heart transplantation. Cardiac surgical or interventional procedures were carried out in four patients. None suffered from malignant arrhythmias or had a cardioverter-defibrillator implanted. Based on the limited information, there are indications that cases with fetal diagnosis of LVHT have a continuing morbidity and mortality, even if they receive appropriate care. Since fetal LVHT is frequently associated with genetic abnormalities, further research about survival and underlying genetic causes is needed.

Surgical management of intrapericardial teratoma in the fetus.

Intrapericardial teratomas often present as life-threatening problems when diagnosed during fetal life. They are large lesions that compress the heart and lungs and can result in tamponade if not treated expeditiously. We present a case of a large teratoma that was managed by prenatal pericardiocentesis followed by surgical resection.

Trisomy 18 and Congenital Heart Disease: Single-Center Review of Outcomes and Parental Perspectives.

BACKGROUND: In patients with trisomy 18, congenital heart surgery is controversial due to anticipated poor patient outcome. Data are lacking regarding clinical outcomes and family opinions about care received. METHODS: A retrospective chart review of patients with trisomy 18 and congenital heart disease from 2005 to 2017 was performed. Patients were grouped into those receiving cardiac intervention (surgery or cardiac catheterization) versus medical management. A telephone survey was used to assess completeness of family counseling provided prior to treatment selection and parental opinions on the care received. RESULTS: Seventeen infants were assessed. In the medical management group (n = 7), there were five deaths at a median age of 1.5 months (range: 1.2-4.1 months) and two survivors aged 29 and 44 months at latest follow-up. In the intervention group (n = 10), cardiac surgery was performed in nine patients at a median age of 4.3 months (0.2-23.4 months) and weight of 3.2 kg (1.5-12.2 kg); catheter intervention was performed in one patient at one week of age. At latest follow-up, seven intervention patients are alive at a median age of 50 months (5-91 months). Survey respondents (n = 12) unanimously stated that their child's quality of life was improved by their specific treatment strategy, that the experience of the parents was enhanced, and that they would choose the same treatment course again. CONCLUSIONS: Surgical repair may be associated with favorable early outcomes and may be judiciously offered in selected circumstances. In this limited experience, parental perceptions were positive regarding the quality of care and overall experience independent of the chosen treatment strategy or eventual outcome.

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma.

PURPOSE: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. EXPERIMENTAL DESIGN: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated. RESULTS: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. CONCLUSIONS: The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

Direct thermal to electrical energy conversion using 9.5/65/35 PLZT ceramics in the ergodic relaxor phase.

This paper reports on direct thermal to electrical energy conversion by performing the Olsen cycle on 9.5/65/35 lead lanthanum zirconate titanate (PLZT). The Olsen cycle consists of two isothermal and two isoelectric field processes in the electric displacement versus electric field diagram. It was performed by alternatively dipping the material in hot and cold dielectric fluid baths under specified electric fields. The effects of applied electric field, sample thickness, electrode material, operating temperature, and cycle frequency on the energy and power densities were investigated. A maximum energy density of 637 ± 20 J/L/cycle was achieved at 0.054 Hz with a 250-µm-thick sample featuring Pt electrodes and coated with a silicone conformal coating. The operating temperatures varied between 3°C and 140°C and the electric field was cycled between 0.2 and 6.0 MV/m. A maximum power density of 55 ± 8 W/L was obtained at 0.125 Hz under the same operating temperatures and electric fields. The dielectric strength of the material, and therefore the energy and power densities generated, increased when the sample thickness decreased from 500 to 250 µm. Furthermore, the electrode material was found to have no significant effect on the energy and power densities for samples subject to the same operating temperatures and electric fields. However, samples with electrode material possessing thermal expansion coefficients similar to that of PLZT were capable of withstanding larger temperature swings. Finally, a fatigue test showed that the power generation gradually degraded when the sample was subject to repeated thermoelectrical loading.

Apical Left Ventriculotomy is Safe in Infants and Young Children Requiring Cardiac Surgery.

OBJECTIVES: Incisions in the left ventricle have previously been associated with increased mortality and morbidity, particularly in infants. In order to determine whether this assumption is still true in the current era, we reviewed our recent experience with apical left ventriculotomy in neonates and infants. METHODS: The records of five consecutive patients requiring a left ventriculotomy between 2007 and 2010 were reviewed. Weight and age ranged from 2.6 to 16 kilograms and 5 days to 2 years. The diagnoses were three multiple ventricular septal defects, one rhabdomyoma, and one apical aneurysm. The primary end point was left ventricular ejection fraction, with other end points being intensive care unit length of stay, time to extubation, inotrope requirement, arrhythmias, and mitral valve function. RESULTS: There were no early or late deaths. Although lower than their preoperative values, early postoperative ejection fractions were greater than 50% in all patients. Two patients required no inotropes, and 3 required only minimal support. Hospital length of stay was 9 ± 7 days for multiple ventricular septal defect patients, with intensive care unit stays of 2 to 5 days. There were no postoperative arrhythmias requiring pharmacological therapy, and one patient had a significant reduction in mitral insufficiency postoperatively. CONCLUSIONS: Based on our experience, we believe that an apical left ventriculotomy does not significantly impair left ventricular function even in small infants, and is not associated with significant morbidity, based on short-term follow-up. Although the long-term effects are still unknown, early results suggest that a left ventriculotomy may safely be used when alternative approaches are inadequate for complex cardiac defects.

Complete repair of Ebstein anomaly in neonates and young infants: a 16-year follow-up.

OBJECTIVE: The purpose of this study was to review the long-term outcome of patients with Ebstein anomaly who underwent complete repair as neonates and young infants. METHODS: Between March 1994 and May 2010, 32 patients (23 neonates and 9 young infants) underwent surgery for Ebstein anomaly. Mean weight was 3.9 ± 2.0 kg (range, 1.9-8.6 kg). The Great Ormond Street Echocardiography score was greater than 1.5 in 22 of the 23 neonates and greater than 1.0 in all infants. All associated cardiac defects were repaired including pulmonary atresia in 15 and ventricular septal defect in 4. Primary outcome measures included (1) early and late survival, (2) freedom from reoperation, (3) durability of tricuspid valve repair, and (4) functional status. RESULTS: Early survival was 78.1% (25/32). There was 1 late death. Fifteen-year survival estimate was 74% ± 8%. For patients with pulmonary atresia, early and late survival was 60% ± 12% (9/15) versus 94.1% (16/17) (P < .05), respectively; for those without pulmonary atresia, early and late survival was 60% ± 12% versus 85% ± 10 (P = .06), respectively. The mean follow-up was 5.9 ± 4.5 years (0.1-16 years). A biventricular repair was achieved in 90.6% (29/32) patients. Median preoperative tricuspid regurgitation was 4/4 and at late follow-up, 1/4. Freedom from reoperation at 15 years was 74% ± 10% for patients undergoing biventricular repair. All survivors are in New York Heart Association class I or II. CONCLUSIONS: Biventricular repair of Ebstein anomaly in symptomatic neonates is feasible with good early and late survival, especially in those without pulmonary atresia. Tricuspid valve repair is durable, and functional status is excellent.

Current Trends in the Management of Neonates With Ebstein's Anomaly.

BACKGROUND: The optimal management strategy for neonates with Ebstein's anomaly is unknown. This analysis was undertaken to assess current trends in the management and prognosis of neonates born with Ebstein's anomaly in the United States, as reflected in an administrative database. METHODS: The Pediatric Health Information System database (40 children's hospitals) was used to review the reported incidence and available data on neonates with Ebstein's anomaly treated in the United States between 2003 and 2007. Primary outcome was hospital survival. Of the 415 patients identified, 257 (62%) did not undergo initial surgical intervention as neonates. Aortopulmonary shunt only was done on 63 patients (15%), single-ventricle palliation on 36 (9%), two-ventricle repair on 16 (4%), heart transplantation in 3 (1%), and a catheter-based intervention or a hybrid palliative approach was applied in 40 (10%). Intergroup comparisons were done using chi-square analyses. RESULTS: Mortality for the entire cohort was 24% (100 of 415). For medically treated patients, this was 22% (56 of 257). For surgically treated and hybrid patients, this was 30% and 23%, respectively (P = NS). CONCLUSIONS: The majority of patients born with Ebstein's anomaly currently do not undergo surgical intervention as neonates. Significant early mortality in this group suggests that certain subsets of patients may benefit from earlier surgical intervention. Among the severely symptomatic neonates who do undergo early surgical intervention, the mortality remains high, irrespective of the surgical approach taken. A multicenter trial may be appropriate to identify strategies to optimize care for these critically ill neonates. Further analysis of risk factors for early mortality is warranted.

Surgical management of unusual cardiac tumors in infants and children.

While most primary tumors of the heart are histologically benign, they are significant space-occupying lesions with serious functional implications for the heart and lungs. Herein, we highlight our experience with the surgical management of selected cardiac tumors in the pediatric population between 2008 and 2010. (1) Intrapericardial teratomas in the fetus can produce fatal tamponade from compression by the attendant pericardial effusion, and a critical life-saving maneuver preoperatively is to drain the effusion prenatally, followed by an expeditious resection after birth. (2) Rhabdomyomas, the most common of the pediatric cardiac tumors, can be intracavitary, large, and associated with the mitral subvalvular apparatus. (3) Cardiac fibromas should be aggressively resected or at least debulked, especially given their propensity for dysrrhythmias. The key to success is as complete a resection as possible, but not at the expense of other normal structures. (4) Complex nonobstructive hypertrophic myopathy can be thought of as a type of neoplastic overgrowth, and aggressive resection of even midcavitary obstructive lesions should be considered as a viable alternative to primary transplantation.

Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma.

PURPOSE: To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. PATIENTS AND METHODS: Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy. RESULTS: Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039). CONCLUSION: The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation.

Controversy exists as to whether platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, can actually protect the heart from postischemic injury. To determine whether endogenous activation of the PAF receptor is cardioprotective, we examined postischemic functional recovery in isolated hearts from wild-type and PAF receptor-knockout mice. Postischemic function was reduced in hearts with targeted deletion of the PAF receptor and in wild-type hearts treated with a PAF receptor antagonist. Furthermore, perfusion with picomolar concentrations of PAF improved postischemic function in hearts from wild-type mice. To elucidate the mechanism of a PAF-mediated cardioprotective effect, we employed a model of intracellular Ca2+ overload and loss of function in nonischemic ventricular myocytes. We found that PAF receptor activation attenuates the time-dependent loss of shortening and increases in intracellular Ca2+ transients in Ca2+ -overloaded myocytes. These protective effects of PAF depend on nitric oxide, but not activation of cGMP. In addition, we found that reversible S-nitrosylation of myocardial proteins must occur in order for PAF to moderate Ca2+ overload and loss of myocyte function. Thus our data are consistent with the hypothesis that low-level PAF receptor activation initiates nitric oxide-induced S-nitrosylation of Ca2+ -handling proteins, e.g., L-type Ca2+ channels, to attenuate Ca2+ overload during ischemia-reperfusion in the heart. Since inhibition of the PAF protective pathway reduces myocardial postischemic function, our results raise concern that clinical therapies for inflammatory diseases that lead to complete blockade of the PAF receptor may eliminate a significant, endogenous cardioprotective pathway.