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Myocardial dysfunction and heart failure are common in pediatric patients with congenital and acquired heart disease. Alkaline phosphatase (AP) has been suggested as a biomarker for myocardial dysfunction after Fontan operation. We hypothesized that pediatric patients with myocardial dysfunction requiring orthotopic heart transplant (OHT) have diminished AP compared to normal. A retrospective review was performed in all patients who underwent OHT at Arkansas Children's Hospital between January 2007 and October 2012. Anatomic diagnoses, therapeutic interventions, and ventricular ejection fraction (EF) were recorded. Z scores for AP levels in the study group were determined by comparing the observed AP levels to age- and gender-matched normative values. T tests were performed to compare the mean AP Z score prior to and after OHT. p values <0.05 were considered statistically significant. During the study period, 124 OHTs were performed. Complete study data were available and analyzed from 71/124 patients (mean age at OHT 3.9 years; 51% female). The mean AP Z score was significantly lower in the study group prior to OHT compared to normal (p < 0.0001). The initiation of ACE inhibitor therapy prior to OHT was associated with a significant increase in AP and the ventricular EF (p < 0.001 for both). Treatment with milrinone was associated with an increase in EF. AP is significantly lower in pediatric patients with myocardial dysfunction prior to OHT compared to normal. AP increases significantly after the initiation of therapies to improve myocardial function. Diminished AP is an indicator of myocardial dysfunction in pediatric patients.

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Aortic complications occur rarely after pediatric orthotopic heart transplantation, but are typically accompanied by catastrophic events. We describe the three cases of major aortic complications in our experience of 329 pediatric heart transplants. This case series and review highlight the important risk factors for aortic complications after heart transplantation.

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BACKGROUND: Patients with end-stage heart failure possess many attributes that place them at risk for prolonged mechanical ventilation (MV). However, there are only limited data on MV support among children after ventricular assist device (VAD) implantation. We report the duration of MV after VAD placement, indications for respiratory support in the postimplantation period, and associated patient factors. METHODS: This single-center retrospective study included 43 consecutive children (aged <18 years) with end-stage heart failure who were supported with a VAD as a bridge to transplantation from January 2005 to December 2011. Multivariable analysis was performed using the multiple Poisson regression model for the duration of MV. RESULTS: Overall, 33% (n = 14) remained on MV until heart transplant or death. Of those requiring pre-VAD extracorporeal membrane oxygenation (ECMO) support, 63% (n = 12 of 19) remained on MV until heart transplant or death compared with 8% (n = 2 of 24) among those not on ECMO before VAD (p < 0.001). Patients with moderate or severe mitral regurgitation while on VAD support had 1.7-times more MV days compared with those with none or trivial on-VAD mitral regurgitation. In addition, previous support on ECMO, those with moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. CONCLUSIONS: Our results suggest that VAD recipients previously supported on ECMO, those with moderate or severe mitral regurgitation, moderate or severe tricuspid regurgitation, and those with only left VAD implants had an increased risk of prolonged MV. Future studies in larger cohorts are necessary to confirm the findings from this single-institutional experience.

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Anthracycline antibiotics are an effective therapy for a variety of neoplastic diseases. Dilated cardiomyopathy is a known risk of their use. Because of the risk of new or recurrent neoplasm with immunosuppression transplantation is often delayed. Our patient developed early cardiomyopathy with congestive heart failure 3 months after completion of chemotherapy. Given the severity of her cardiac symptoms the decision was made to proceed with heart transplantation in the short term after completion of her chemotherapy. We report the success to 1 year of this decision and discuss the implications of her genetic and oncologic diagnoses in this clinical scenario.

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BACKGROUND: Ventricular assist devices (VADs) are increasingly being used in pediatric patients to provide long-term cardiac support. One potential complication of VAD therapy is the development of antibodies directed against human leukocyte antigens (HLA). This phenomenon has not been well described with the Berlin Heart EXCOR VAD, the most commonly used VAD in pediatric patients. METHODS: The records of all pediatric patients undergoing VAD support using the Berlin Heart device at our institution between April 2005 and August 2011 were reviewed retrospectively. Demographic and clinical data regarding the VAD course were collected. Assessment of anti-HLA antibodies was performed using Luminex, and antibodies were quantified using mean fluorescence intensity (MFI). Assessment for anti-HLA antibodies was performed before VAD implantation and in serial fashion after VAD implantation. Clinically significant anti-HLA antibodies (sensitization) were defined by an MFI of more than 1000. RESULTS: Thirty-six patients were supported with the Berlin Heart VAD; 13 met inclusion criteria. The majority (85%) carried the diagnosis of dilated cardiomyopathy. Evidence of sensitization pre-VAD was found in 69%; new-onset sensitization (the development of new antibodies on VAD) occurred in 69%. All patients survived to transplantation. In two patients, the retrospective crossmatch was positive, but only in one patient was the crossmatch positive for antibodies formed while on VAD. CONCLUSIONS: Using Luminex and MFI quantification, anti-HLA antibodies are common before VAD implantation in pediatric patients. While on VAD support, new anti-HLA antibodies formed in a majority, but the immediate impact of these antibodies appears to be limited.

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BACKGROUND: The use of ventricular assist devices (VADs) in children is challenging because of small patient size, frequent structural heart disease, and the need for biventricular assist devices. This report describes the role of echocardiography in the management of children supported by VADs. METHODS: A retrospective review of the records of all pediatric patients who underwent VAD placement between May 2005 and May 2011 was performed to collect demographics, cardiac diagnoses, details of VADs, and transthoracic and transesophageal echocardiographic findings from the time of initial diagnosis until VAD explantation. RESULTS: The study included 32 patients (median age, 3 years; age range, 20 days to 16 years; median weight, 12.3 kg; weight range, 3.5-60 kg), 20 with left ventricular assist devices and 12 with biventricular assist devices. Diagnoses included dilated cardiomyopathy or myocarditis (n = 27) and congenital heart disease (n = 5). The median duration of support was 12 days (range, 1-141 days). Patients with decreased right ventricular function were 8 times more likely to undergo biventricular assist device placement compared with those with normal right ventricular function (P = .026). Pre-VAD intracardiac shunts were identified in 11 patients and intracardiac thrombus in one patient. Cardiac chamber dimensions and mitral insufficiency were significantly reduced after VAD implantation. Postimplantation pericardial effusions were recognized in 16 patients and pericardial hematomas in 12 patients. CONCLUSIONS: Echocardiography is invaluable in the management of pediatric patients receiving VADs. It is helpful in pre-VAD assessment, guiding intraoperative device placement, recognizing VAD dysfunction, and identifying postimplantation complications.

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Although parvovirus B19 (PVB19) currently is the most common cause of viral myocarditis, limited pediatric data exist. Whereas other viruses infect cardiomyocytes, PVB19 targets coronary endothelium, leading to myocardial ischemia and dysfunction. A retrospective review investigated patients with polymerase chain reaction (PCR)-verified PVB19 myocarditis at Texas Children's Hospital and Arkansas Children's Hospital (January 2005 to August 2008). The primary end points of the study were transplant-free survival and circulatory collapse (death, mechanical support, or transplantation). For the 19 patients identified (age, 6 months to 15 years), the most common presenting symptoms were respiratory and gastrointestinal. At admission, all the patients demonstrated ventricular dysfunction requiring inotropic support (median ejection fraction, 24 %; median left ventricle end-diastolic diameter [LVEDD] z-score, 4.6). Whereas T-wave abnormalities were common, ST elevation was evident in five patients (two died and three required transplantation). Serum B-type natrietic peptide was elevated in all 12 patients tested (range, 348-8,058 pg/ml), and troponin I was high in 7 of 9 patients (range, 0.04-14.5 ng/ml). Of the 15 patients with circulatory collapse, nine received mechanical support, eight underwent successful transplantation, and five died. Only six patients (32 %) experienced transplant-free survival, and five patients had full recovery of function at discharge. In the transplant-free survival group, ST changes on presenting electrocardiography were less likely (p = 0.03), and the admission LVEDD z-score tended to be lower (3.3 vs 5.6; p = 0.08). In children, PVB19 myocarditis causes significant mortality and morbidity. Although mechanical intervention can support patients in the initial stage of decompensated heart failure, patients with PVB19 myocarditis often demonstrate persistent dysfunction requiring medical therapy and transplantation.

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The pseudophosphatase MK-STYX (mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding protein) has been implicated in the stress response pathway. The expression of MK-STYX inhibits the assembly of stress granules, which are cytoplasmic storage sites for mRNA that form as a protective mechanism against stressors such as heat shock, UV irradiation and hypoxia. Furthermore, MK-STYX interacts with a key component of stress granules: G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1). Because G3BP-1 dephosphorylation at Ser149 induces stress granule assembly, we initially hypothesized that the inhibition of stress granules by MK-STYX was G3BP-1 phosphorylation-dependent. However, in the present study, using MK-STYX constructs and G3BP-1 phosphomimetic or nonphosphorylatable mutants, we show that MK-STYX inhibits stress granule formation independently of G3BP-1 phosphorylation at Ser149. The introduction of point mutations at the 'active site' of MK-STYX that convert serine and phenylalanine to histidine and cysteine, respectively, is sufficient to generate an active enzyme. In separate experiments, we show that this active mutant, MK-STYX(active), has opposite effects to wild-type MK-STYK. Not only does MK-STYX(active) induce stress granules, but also it has the capacity to dephosphorylate G3BP-1. Taken together, these results provide evidence that the pseudophosphatase MK-STYX plays a key role in the cellular response to stress.

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This retrospective observational study aimed to evaluate the safety and efficacy of dexmedetomidine (DEX) for children with heart failure. The study was conducted in the cardiovascular intensive care unit (CVICU) of a single, tertiary care, academic children's hospital. A retrospective review of the charts for all children (up to 18 years of age) with signs and symptoms consistent with congestive heart failure who received DEX in our CVICU between April 2006 and April 2011 was performed. The patients were divided into two groups for study purposes: the DEX group of 21 patients, who received a DEX infusion together with other conventional sedation agents, and the control group of 23 patients, who received conventional sedation agents without the use of DEX. To evaluate the safety of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), and inotrope score. To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions in both the DEX and control groups were examined. The numbers of rescue boluses for each category before the initiation of sedative infusion and during the sedative infusion also were examined. The baseline characteristics of the patients in the two groups were similar. There was no effect of DEX infusion on heart rate, MAP, or inotrope score at the termination of infusion. The daily amount of midazolam administered was significantly less during the last 24 h of DEX infusion in the DEX group than in the control group (p = 0.04). The daily amount of morphine infusion did not differ between the DEX and control groups during any period. The numbers of sedation and analgesic rescue boluses were lower in DEX group throughout the infusion. No other significant side effects were noted. Two patients in the DEX group had a 50 % or greater drop in MAP compared with baseline in the first 3 h after initiation of DEX infusion, whereas one patient had a 50 % or greater drop in heart rate compared with baseline in the first 3 h after initiation of DEX infusion. Administration of DEX for children with heart failure appears to be safe but should be used cautiously. Furthermore, DEX use is associated with a decreased opiate and benzodiazepine requirement for children with heart failure.

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Use of high-risk or marginal donors is the most viable short-term means to boost the organ supply and bridge the widening gap between the number of patients on the waiting list for organ transplantation and the insufficient numbers of organ donors. Expansion of the donor pool requires an understanding of the impact on survival likely to result from extending one or more high risk factors. Use of extended donor pool results in shorter waiting list times and limits the morbidity and mortality associated with long-term mechanical support needed to support diseased organs. In this report, we present one such example of expanding donor pool in which a pediatric patient donated a solid organ after two heart transplants and successful use of ECMO and VAD.

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Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value.

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BACKGROUND: High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. METHODS: Patients received four intravenous dose of bortezomib (1.3 mg/m(2)) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. RESULTS: AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. CONCLUSIONS: Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

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We hypothesized that use of Schwartz formula underestimates the prevalence of CKD in PHT recipients. This study determined the prevalence and risk factors for CKD in PHT using novel methods-serum cystatin C, CKiD formula, Revised Schwartz formula, s- and u-NGAL. Serum BUN, creatinine, cystatin C and s- and u-NGAL were measured after prospective enrollment. Schwartz formula GFR was compared with novel methods. CKD was defined as CKiD GFR < 90 mL/min/1.73 m(2) . The s- and u-NGAL were compared between those with and without CKD. Potential risk factors for CKD were analyzed. Seventy-nine patients (46 male children or boys), mean age 9.9 ± 5.8 yr formed the study cohort. The prevalence of mild and moderate CKD was 2- to 3-fold higher using novel methods compared to Schwartz formula. u-NGAL and u-NGAL/Cr were significantly higher in patients with CKD. u- and s-NGAL had negative correlation with estimates of GFR. Women were at a higher risk for CKD (odds ratio 8.7) as was longer duration since transplant (p = 0.009). In conclusion, use of novel methods of GFR estimation unmasked 2- to 3-fold increased prevalence of CKD in PHT. Women and those with longer duration since transplant are at higher risk for CKD.

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The purpose of the study is to determine the association of Doppler tissue imaging (DTI) and catheter-derived measures with rejection in pediatric heart transplant (PHT) recipients and to determine any correlation between DTI and catheter-derived measurements. Sixty echocardiograms were prospectively performed in 37 PHT recipients at the time of surveillance cardiac biopsy. During right-heart cardiac catheterization, sequential pressures of the right heart and pulmonary capillary wedge pressures (PCWP) were measured. DTI was performed to obtain peak systolic (S'), early (E') and late (A') diastolic velocities (cm/s) at tricuspid annulus, septum and mitral annulus. Septal S' and tricuspid annular A' were associated with rejection, but had low sensitivity and specificity. Elevated lateral mitral E/E' did not predict rejection. The mean pulmonary capillary wedge pressure (PCWP) and cardiac index were similar in those with and without rejection. The lateral mitral and septal E/E' did not correlate with PCWP. Some DTI-derived measures were altered during rejection, but were not clinically useful predictors of rejection. Catheter-derived measures were not significantly altered during rejection and did not correlate with DTI-derived measures. None of these measures can replace the current practice of performing cardiac biopsy for surveillance of rejection.

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BACKGROUND: Somatic growth pattern in infants undergoing staged palliation for hypoplastic left heart syndrome (Norwood procedure [NP], stage 2 palliation [S2P], and Fontan procedure [FP]) during transition toward a more energy efficient series circulation is not well understood. OBJECTIVES: We sought to determine growth pattern in these infants and factors influencing it. METHODS: Patients who underwent NP since 2001 and survived at least 1 year after S2P were followed until FP or death/heart transplantation (n = 46). Weight for age z-scores (WAZ) were measured prior to NP; at initial discharge; prior to S2P; at four time periods after S2P; and prior to FP. Impact of gender, race, era of NP, anatomic subtype, NP shunt type, gastrostomy, home-surveillance program (daily weights and pulse oximetry), and interstage oxygen saturation on WAZ was evaluated. RESULTS: Repeated measures anova showed a significant change in WAZ across time periods (P < 0.0005), with a significant decline from Pre-NP to Pre-S2P (P < 0.0005) and steady increase from Pre-S2P to Pre-FP (P= 0.016). None of the factors evaluated had a significant effect on this growth pattern. Length of hospital stay after NP was negatively correlated with WAZ at discharge (P= 0.001), but not for other time periods. Intervals from discharge to S2P and NP to S2P interval did not correlate with WAZ. CONCLUSION: Somatic growth is significantly impaired after NP but recovers steadily following S2P, as the patient transitions toward separated series circulation. Earlier S2P may lead to earlier resumption of normal growth in this critical period of early infancy.

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There is a paucity of literature assessing the burden of bone loss in PHT recipients. We sought to describe the bone mineral status in PHT recipients by doing a retrospective medical record review of those who underwent evaluation of BMD when clinically indicated. Data collected included patient demographics, BMD evaluations, serum calcium, phosphorus, alkaline phosphatase, cumulative steroid dose, osseous complications and their management. Of 149 PHT recipients, 26 underwent BMD evaluation. This evaluation was done at a median of 3.4 yrs after PHT. There total serum calcium, phosphorus and alkaline phosphatase were similar at transplant and BMD study. The median BMD Z-scores were: whole body -0.09 (1.5 to -5.13) and lumbar spine -1.1 (1.5 to -5.16). Bone loss (Z-score <-1) was present in 14 (53.8%). Three patients had spinal fractures and/or avascular necrosis of various bones. Treatment included calcitrol and bisphosphonates; and vertebroplasty for spinal fracture. Bone loss was present in a significant proportion of PHT recipients and may be associated with fractures and avascular necrosis. More than half of our "at risk" cohort had bone loss. Careful surveillance of these patients should be performed to prevent morbidity.

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PCI has been used for palliation of CAV in adults, but there are limited data available in children. We sought to evaluate our experience with PCIs for CAV in pediatric heart transplant recipients. Retrospective review of the medical records of all four patients who were diagnosed with CAV, including demographic data and catheterization reports was performed. Of the 149 pediatric heart transplant recipients followed at our institution, 10 were identified with CAV. Four of these 10 underwent 12 PCI procedures for CAV. One donor heart had documented coronary artery disease. Two patients had significant risk factors for coronary artery disease including morbid obesity, hyperlipidemia, and systemic hypertension. PCI involved deployment of bare metal stents (n = 2), paclitaxel-eluting stent (n = 6), and sirolimus-eluting stents (n = 4) with procedural success in all and no early or late mortality. One procedure was complicated by coronary dissection that was successfully treated with stent placement. One patient has been re-transplanted while the other three are not candidates for re-transplantation and have remained asymptomatic as palliation with PCI. PCI using coronary stents is a safe and effective palliative measure for CAV in pediatric heart transplant recipients.

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For children requiring mechanical circulatory support as a bridge to cardiac transplantation in North America, options previously were limited to extracorporeal membrane oxygenation (ECMO) or centrifugal pump ventricular assist, both of which were suitable for only very short term application and were associated with significant complications and limitations. The Berlin Heart EXCOR ventricular assist device (VAD) was recently introduced into practice in North America to address this deficiency. We report a preliminary single center experience with the EXCOR in 17 children, 13 who received only a left-sided pump and four who required biventricular support. Before EXCOR placement, six patients were on ECMO, and one was on a centrifugal VAD. Eleven children were bridged to transplantation, one was bridged to recovery, and one remains on support. Three children died during support and one died after explantation. There was one late death nearly 2 years after transplant. Complications included stroke in seven patients, two of which were ultimately fatal. Five patients required re-operations for bleeding or evacuation of hematoma. Despite a disappointing rate of neurologic morbidity, our preliminary experience with the EXCOR has been very encouraging.

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We report a 15-year-old male patient who developed type II heparin-induced thrombocytopenia (HIT) after 6 weeks of heparin administration and placement of a Berlin Heart Excor left ventricular assist device (LVAD).

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