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issn:0172-0.43
1.  Neurodevelopmental Outcomes for Children With Hypoplastic Left Heart Syndrome at the Age of 5 Years 
Pediatric cardiology  2013;34(7):1597-1604.
This study aimed to determine the neurodevelopmental (ND) outcome for children with hypoplastic left heart syndrome (HLHS) at early school age. English-speaking patients who underwent the Norwood procedure between 2000 and 2005 were eligible at 4–6 years of age for ND testing. Of the 72 eligible patients, 44 (61 %) agreed to participate, and 37 completed ND testing before the close of the study. Three subjects were excluded from analyses due to late stroke. The ND testing included intelligence, visual motor integration, memory and motor and language skills. Parents and teachers completed measures of behavior and attention problems. Subjects’ scores and parent/teacher ratings were converted to z-scores and compared with test norms. Higher scores on child measures represent better outcomes, whereas higher scores on parent and teacher rating scales indicate more problems. The average ND performance of the tested cohort fell within one standard deviation of the test norms for all measures. However, the subjects performed significantly lower than the test norms on measures of visual-motor integration, fine motor skills, memory, and word structure (z = −0.42 to −0.54; p < 0.005). On the parent and teacher completed measures, the subjects scored higher than the test norms on attention problems (z = 0.40–0.62; p < 0.005). Although the overall ND performance of the cohort was normal, the subjects showed relative weakness in visual motor and attention skills. Ongoing developmental monitoring of these children is recommended to guide interventions that may improve individual outcomes and to assess the impact of changes in clinical management strategies on functional outcomes.
doi:10.1007/s00246-013-0679-3
PMCID: PMC3982227  PMID: 23503929
Congenital heart disease/defects; Developmental outcomes; Hypoplastic left heart syndrome
2.  Cranial Irradiation as an Additional Risk Factor for Anthracycline Cardiotoxicity in Childhood Cancer Survivors: An Analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study 
Pediatric cardiology  2012;34(4):826-834.
Background
Anthracycline-treated childhood cancer survivors suffer cardiac damage that results in decreased left ventricular (LV) mass, leading to increased LV wall stress, which underlies their greater risk of cardiomyopathy. Many of these survivors are also at risk of growth hormone (GH) abnormalities from cranial irradiation exposure though it is unknown if such exposure is associated with cardiotoxicity.
Methods
Echocardiograms and insulin-like growth factor-1 (IGF-1), a marker of GH, were measured in 130 anthracycline-treated childhood cancer survivors, 59 of whom had been exposed to cranial irradiation, a mean 10 years from cancer diagnosis. Echocardiographic parameters and IGF-1 were standardized relative to age or body-surface area using data from sibling controls and expressed as the percent difference from normal.
Results
After adjusting for other risk factors, survivors exposed to cranial irradiation had an additional 12% decrease in LV mass compared to unexposed survivors (P<.01), and an additional 3.6% decrease in LV dimension (P=.03). Survivors exposed to cranial irradiation also had a 30.8% decrease in IGF-1 relative to normal, which was greater than the 10.5% decrease in unexposed survivors (P<.01).
Conclusions
In anthracycline-treated childhood cancer survivors, a mean 10 years from diagnosis, those with cranial irradiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation was also associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect suggesting that GH replacement therapy may help prevent the development of cardiotoxicity.
doi:10.1007/s00246-012-0539-6
PMCID: PMC3594453  PMID: 23080542
Cardiomyopathy; Anthracyclines; Cranial Irradiation; Cancer; Survivors
3.  Acute Pulmonary Vasodilator Testing With Inhaled Treprostinil in Children With Pulmonary Arterial Hypertension 
Pediatric cardiology  2012;34(4):1006-1012.
Acute pulmonary vasodilator testing (AVT) is essential to determining the initial therapy for children with pulmonary arterial hypertension (PAH). This study aimed to report the initial experience with inhaled treprostinil used for AVT in children with PAH and to evaluate the hemodynamic change after inhaled treprostinil compared with inhaled nitric oxide. This prospective cohort study was designed for 13 children who underwent AVT with inhaled treprostinil or oxygen plus inhaled nitric oxide (iNO) during catheterization. Inhaled treprostinil was delivered during cardiac catheterization by adapting the Optineb ultrasonic nebulizer via either a flow-inflating bag or the manual mode of the anesthesia system. The median age of the patients was 10 years (range 4–17 years). The etiologies of PAH included idiopathic PAH and associated PAH. All the patients tolerated inhaled treprostinil without marked clinical worsening and received six or nine breaths (36 or 54 µg) of treprostinil. The median of the total treprostinil doses was 1.53 µg/kg (range 0.71–2.89 µg/kg). Inhaled treprostinil was administrated via an endotracheal tube (n = 8), anesthesia mask (n = 3), or laryngeal mask airway (n = 2). Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index compared with baseline. Three adverse events were reported after inhaled treprostinil, including cough and mild to moderate hypotension with higher doses. All adverse events resolved without any intervention. This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT.
doi:10.1007/s00246-012-0597-9
PMCID: PMC3608847  PMID: 23184020
Acute pulmonary vasodilator testing; Children; Iloprost; Inhaled treprostinil; Nitric oxide; Pulmonary arterial hypertension
4.  Sudden Unexplained Cardiac Arrest in Apparently Healthy Children: A Single Center Experience 
Pediatric cardiology  2012;34(3):639-645.
Objective
To determine the causes of sudden cardiac arrest (SCA) in apparently healthy children in a single center in the era of primary prevention (screening questionnaire, SQ) and secondary prevention (automated external defibrillator, AED and automated implantable cardioverter defibrillator, AICD).
Study Design
Any child (0–18 year’s age) without prior known disease except for attention deficit disorder who underwent out-of-the hospital cardiopulmonary resuscitation was included in the study as SCA. Using retrospective chart review we evaluated the efficacy of the SQ, electrocardiogram (EKG), chest roentgenogram (CXR) and an echocardiogram.
Results
We found 44 out of 6,656 children admitted to intensive care with SCA; an AED was used in 39%, AICD placed in 18% and survival to hospital discharge was 50%. The etiology for SCA was identified in 57% of the cases, mostly in those above one year of age and among these the majority of had a cardiac etiology (50%) while 7% had rupture of an arteriovenous malformation. Stimulant medication use was seen in 11% of the SCA. In the best case scenario of hypothesized primary prevention, a prior SQ, CXR, EKG and echocardiogram may have detected 18%, 9%, 23% and 16% of at-risk cases respectively and 32% may have been detected with EKG and SQ together. Based on a historical control cohort, a positive EKG was significantly higher in children with SCA (p = 0.014).
Conclusion
An EKG along with a screening SQ may be more effective in identifying children who are potentially at-risk for SCA than a SQ alone.
doi:10.1007/s00246-012-0516-0
PMCID: PMC3566361  PMID: 23052663
Stimulants; attention deficit hyperactivity disorder; pseudoephedrine; arteriovenous malformation; sudden cardiac death
5.  Prenatal Diagnosis of Congenital Heart Disease and Birth Outcomes 
Pediatric cardiology  2012;34(3):597-605.
This study was undertaken to examine the impact that prenatal diagnosis of congenital heart disease (CHD) has on birth and early neonatal outcomes. The prevalence of prenatally diagnosed CHD has risen over the past decade, but the effect that prenatal diagnosis of CHD has on peripartum decisions remains unclear. No consensus exists on the effect of prenatal diagnosis on neonatal outcomes. Between January 2004 and July 2009, a retrospective chart review of all neonates with CHD admitted to our institution’s neonatal intensive care unit was conducted. Obstetric and postnatal variables were collected. Among the 993 subjects, 678 (68.3 %) had a prenatal diagnosis. A prenatal diagnosis increased the odds of a scheduled delivery [odds ratio (OR) 4.1, 95 % confidence interval (CI) 3.0–5.6] and induction of labor (OR 11.5, 95 % CI 6.6–20.1). Prenatal diagnosis was not significantly associated with cesarean delivery when control was used for maternal age, multiple gestation, and presence of extracardiac anomaly. Mean gestational age had no impact on prenatal diagnosis, but prenatal diagnosis was associated with increased odds of delivery before a gestational age of 39 weeks (OR 1.5, 95 % CI 1.1–1.9) and decreased odds of preoperative intubation (OR 0.5, 95 % CI 0.3–0.6). Prenatal diagnosis did not have an impact on preoperative or predischarge mortality. Prenatal diagnosis was associated with increased odds of a scheduled delivery, birth before a gestational age of 39 weeks, and a decreased need for invasive respiratory support. Prenatal diagnosis of CHD was not associated with preoperative or predischarge mortality.
doi:10.1007/s00246-012-0504-4
PMCID: PMC3647457  PMID: 23052660
Birth; Congenital heart disease; Neonatal; Obstetrical; Outcomes; Prenatal diagnosis
6.  Acute-Phase Reactants and a Supplemental Diagnostic Aid for Kawasaki Disease 
Pediatric cardiology  2010;31(8):1209-1213.
The diagnosis of acute Kawasaki disease (KD) is based on characteristic clinical signs and not on a specific diagnostic test. The authors performed a comprehensive evaluation of acute-phase reactants in KD to determine which of the acute-phase reactants would most accurately distinguish KD from other febrile illnesses. Blood was collected from 218 cases of febrile children with KD (64 cases); bacterial pneumonia (74 cases); hand, foot, and mouth disease (31 cases); and upper respiratory tract infection (49 cases) in acute-stage illness before any therapy. The demographics, body temperature, and laboratory markers including white blood cell count, red blood cell count, and levels of hemoglobin, platelets, C-reactive protein, haptoglobin, apolipoprotein A-I, and apolipoprotein B were evaluated. Using post hoc analysis, the platelet count (103/μl) and haptoglobin/apolipoprotein A-I ratio were significantly higher for the KD patients (404.64 ± 161.68, P = 0.004; 4.74 ± 2.73, P < 0.001) than for the other groups including patients with pneumonia (272.76 ± 115.07, 2.03 ± 1.88); hand, foot, and mouth disease (274 ± 105.9, 2.24 ± 1.19); and upper respiratory tract infection (b282.06 ± 107.72, 1.4 ± 0.98). The best cutoff value of the haptoglobin/apolipoprotein A-I ratio obtained from receiver operating characteristics (ROC) curves for KD was 2 (area under the ROC curve, 0.88; 95% confidence interval, 0.801–0.955), with a sensitivity of 89.7% and a specificity of 85.6% for detecting KD. Our data indicate that the serum haptoglobin/apolipoprotein A-I ratio could be a useful supplemental laboratory marker for the acute phase of KD.
doi:10.1007/s00246-010-9801-y
PMCID: PMC3933282  PMID: 20957478
Acute-phase reactants; Apolipoprotein A-I; Apolipoprotein B; Haptoglobin; Haptoglobin/apolipoprotein A-I ratio; Kawasaki disease
7.  A Predictive Model for Neurodevelopmental Outcome Following the Norwood Procedure 
Pediatric cardiology  2012;34(2):327-333.
Neurodevelopmental outcomes following the Norwood procedure for single right ventricular lesions are worse than those in the normal population. It would be valuable to identify which patients at the time of Norwood discharge are at greatest risk of neurodevelopmental impairment later in childhood. As such, we sought to construct and validate a model to predict poor neurodevelopmental outcome using variables readily available to the clinician. Using data from 14-month neurodevelopmental outcome of the Single Ventricle Reconstruction (SVR) trial, a Classification and Regression Tree (CART) analysis model was developed to predict severe neurodevelopmental impairment, defined as a Psychomotor Development Index (PDI) of <70 on the Bayley Scales of Infant Development®-II. The model was then validated using data from subjects enrolled in the Infant Single Ventricle (ISV) trial.
PDI scores were <70 in 138 of 313 subjects (44%). Predictors of PDI<70 were: post-Norwood length of ICU stay >46 days, genetic syndrome or other anomalies, birth weight <2.7 kg, additional cardiac surgical procedures, and use of ≥5 medications at hospital discharge. Using these risk factors, the CART model correctly identified 75% of SVR subjects with PDI<70. When the CART model was applied to 70 subjects from the ISV trial, the correct classification rate was 67%.
This model of variables from the Norwood hospitalization can help identify infants at risk for neurodevelopmental impairment. However, given the overall high prevalence of neurodevelopmental impairment and the fact that nearly one-third of severely affected children would not have been identified by these risk factors, close surveillance and assessment for early intervention services is warranted for all infants following the Norwood procedure.
doi:10.1007/s00246-012-0450-1
PMCID: PMC3505274  PMID: 22864647
Neurodevelopment; congenital heart; outcomes
8.  Demographic Characteristics and Estimated Prevalence of Fontan-Associated Plastic Bronchitis 
Pediatric cardiology  2012;34(2):256-261.
Plastic bronchitis (PB) is a poorly understood disease that can complicate any underlying pulmonary disease. However, it appears to most often occur in patients with surgically palliated congenital heart disease, particularly after the Fontan procedure. Few data exist about the prevalence and etiology of PB in this population. In an effort to establish data about prevalence, we conducted a retrospective study of an existing Fontan surgery database (n = 654) comprised of data, including sex, age at date of surgery, alive/dead status, New York Heart Association classification at last follow-up, right-ventricular end-diastolic pressure and pulmonary artery pressure before Fontan surgery, and the presence of a Fontan fenestration. An initial medical record review of 173 patients in the database who were followed at the University of Michigan identified seven patients with PB resulting in an estimated prevalence of 4 %. Subsequently, 14 % of 211 surveyed patients reported that they presently expectorate mucus or fibrin plugs (casts). Demographic and clinical variables did not differ between patients with or without possible PB. Collectively, these findings suggest that Fontan patients presently with PB may range from 4 to 14 %, indicating potential under-diagnosis of the disease. There were no remarkable physical or hemodynamic indicators that differentiated patients with or without possible PB. These data also highlight the need for more elaborate, prospective studies to improve our understanding of PB pathogenesis so that more definitive diagnostic criteria for this devastating disease can be established and its prevalence more accurately determined.
doi:10.1007/s00246-012-0430-5
PMCID: PMC3586576  PMID: 22797520
Congenital heart disease; Hypoplastic left heart syndrome; Fontan procedure adverse effects
9.  Extreme clinical variability of dilated cardiomyopathy in two siblings with Alström syndrome 
Pediatric cardiology  2012;34(2):455-458.
Alström syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report on two brothers, 2 and 3 years of age, diagnosed with Alström syndrome who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intra-familial variability. While cardiomyopathy in the older sibling has mainly resolved allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intra-familial variability of ALMS, mainly in the natural course of cardiac disease.
doi:10.1007/s00246-012-0296-6
PMCID: PMC3779600  PMID: 22447358
Alström syndrome; dilated cardiomyopathy; autosomal recessive; ALMS1 gene
10.  The Role of Serum Response Factor in Early Coronary Vasculogenesis 
Pediatric cardiology  2010;31(3):10.1007/s00246-009-9614-z.
doi:10.1007/s00246-009-9614-z
PMCID: PMC3866703  PMID: 20091302
11.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998 and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index < 70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small for gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18–22 months’ corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20% of infants survived without NDI.
doi:10.1007/s00246-012-0375-8
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
12.  Histopathologic Evaluation of Patent Ductus Arteriosus Stents After Hybrid Stage I Palliation 
Pediatric cardiology  2011;32(4):10.1007/s00246-010-9870-y.
The aim of this study was to determine the histopathology of patent ductus arteriosus (PDA) in-stent stenosis after hybrid stage I palliation. The hybrid approach to palliation of hypoplastic left heart syndrome can be complicated by the development of in-stent stenosis of the PDA. This may obstruct retrograde aortic arch flow, decrease systemic circulation, and lead to interstage interventional procedures. Stented PDA samples removed from eight patients undergoing comprehensive stage II repair were examined by way of radiography and histochemistry (hematoxylin and eosin, Movat pentachrome, α-smooth muscle actin, and proliferating cell nuclear antigen). A retrospective chart review of the patients was also performed. PDA stents were in place in the PDA for a mean period of 169 ± 28 days in patients who had a mean age of 176 ± 30 days at the time of stent removal. Stent deployment caused chronic inflammation, caused fibrin deposition, and induced vascular smooth muscle–cell (VSMC) proliferation in the area immediately surrounding the stent struts. The neointimal region was composed largely of smooth muscle cells that appeared to be fully differentiated by the lack of PCNA staining. Neointimal thickening occurs in the PDA after stent placement for hybrid palliation of HLHS and is the result of inflammation, extracellular matrix deposition, and smooth muscle–cell proliferation in the peristrut region. This finding suggests that proliferating VSMCs in the peristrut region may provide the impetus for inward neointimal formation and therefore the manifestation of in-stent stenosis.
doi:10.1007/s00246-010-9870-y
PMCID: PMC3822434  PMID: 21298382
Ductus arteriosus; Stent; Neointima; In-stent stenosis
13.  Predictors of Retrograde Aortic Arch Obstruction After Hybrid Palliation of Hypoplastic Left Heart Syndrome 
Pediatric cardiology  2010;32(1):10.1007/s00246-010-9820-8.
A potential complication after hybrid stage 1 palliation for hypoplastic left heart syndrome (HLHS) is retrograde aortic arch obstruction (RAAO). This can lead to increased morbidity and unplanned surgical or interventional procedures in the interstage period. This study aimed to identify potential predictors of RAAO by analyzing initial echocardiograms and angiograms before hybrid stage 1 palliation. For this study, 96 patients who underwent hybrid stage 1 palliation between July 2002 and July 2009 were reviewed, 68 of which had standard HLHS and met the inclusion criteria. The initial echocardiogram, hybrid stage 1 angiograms, and follow-up echocardiograms were reviewed. Anatomic and hemodynamic measurements were obtained by both modalities, and comparisons were made between those who developed RAAO and those who did not. Of the 68 patients, 20 (29%) had RAAO. The mean aortic root size was smaller for the patients who had RAAO (3.6 vs 4.4 mm; p = 0.036). The angiographic angle between the aortic isthmus and the patent ductus arteriosus (PDA) was significantly larger in the RAAO group (86° vs 63°; p = 0.008). The retrograde aortic arch velocities were higher in the RAAO group. Patients with RAAO have a smaller aortic root and higher retrograde velocities on initial echocardiogram. Patients with RAAO show a larger angle between the retrograde arch and PDA on angiogram. Because RAAO is an important potential complication after hybrid stage 1 palliation for HLHS, identification of predictors of RAAO may lead to improved care and outcome for patients with RAAO.
doi:10.1007/s00246-010-9820-8
PMCID: PMC3818711  PMID: 20957474
Hybrid stage 1 palliation; Hypoplastic left heart syndrome; Retrograde aortic arch obstruction
14.  Food and Drug Administration (FDA) Postmarket Reported Side Effects and Adverse Events Associated with Pulmonary Hypertension Therapy in Pediatric Patients 
Pediatric cardiology  2013;34(7):1628-1636.
Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.
doi:10.1007/s00246-013-0688-2
PMCID: PMC3783558  PMID: 23532466
Adverse drug events; Pediatrics; Pulmonary; hypertension
15.  Response to a Single Dose of Sildenafil in Single-Ventricle Patients: An Echocardiographic Evaluation 
Pediatric cardiology  2012;34(7):1739-1742.
New evidence of increased phosphodiesterase-5 (PDE-5) in hypertrophied human myocardium suggests that sildenafil, a selective PDE-5 inhibitor, may improve muscle contraction and therefore improve ventricular function. The purpose of this study was to compare ventricular function as assessed by echocardiography in 10 surgically palliated single-ventricle patients at baseline and again after a single dose of sildenafil. The velocity time integral of the ventricular outflow tract was increased 2 h after sildenafil administration (p = 0.01), thus suggesting an improvement in cardiac output.
doi:10.1007/s00246-012-0415-4
PMCID: PMC3783569  PMID: 22806713
Congenital heart disease; Fontan; Pediatric; Univentricular heart
16.  Quantitative Evaluation of Hemodynamics in the Fontan Circulation: A Cross-Sectional Study Measuring Energy Loss In Vivo 
Pediatric Cardiology  2013;35:361-367.
Flow energy loss (EL) at the Fontan anastomosis has been thought to reflect flow efficiencies and to influence on hemodynamics in the Fontan circulation and has been often discussed in numerical studies. However, in vivo EL measurements have to date not been reported. We directly measured EL in the Fontan circulation and examined the relationship between the structural configuration and EL, as well as the influence of EL, on the hemodynamics in the Fontan circulation. We performed a catheterization study measuring simultaneous pressure and flow velocity to calculate EL in nine patients (mean age 2.3 ± 0.3 years) 1 year after the Fontan procedure. The measured EL was 9.66 ± 8.50 mW. One patient with left pulmonary artery stenosis recorded the highest EL (17.78 mW), and one patient with bilateral superior vena cava and left phrenic nerve palsy recorded the second highest EL (14.62 mW). EL significantly correlated with time constant tau and weakly with max-dp/dt during the isovolumic diastolic phase (r = 0.795 and −0.574, respectively). EL also correlated with max-dp/dt during the isovolumic systolic phase (r = 0.842) but not with ejection fraction or systemic blood flow (r = 0.384 and −0.034, respectively). In conclusion, inefficient structural configuration and phrenic nerve palsy seem to be related with increased in EL at the Fontan anastomosis. Although these preliminary findings also suggest that EL is associated with an impaired relaxation of the ventricle, a long-term study with a large population is warranted to reach such a definitive conclusion.
doi:10.1007/s00246-013-0783-4
PMCID: PMC3897874  PMID: 24002356
Energy loss; Fontan circulation; Structural configuration; Diastolic function
17.  Remote Monitoring of Cardiovascular Implantable Devices in the Pediatric Population Improves Detection of Adverse Events 
Pediatric Cardiology  2013;35:301-306.
With the exponential growth of cardiovascular implantable electronic devices (CIEDs) in pediatric patients, a new method of long-term surveillance, remote monitoring (RM), has become the standard of care. The purpose of this study was to determine the usefulness of RM as a monitoring tool in the pediatric population. A retrospective review was performed of 198 patients at the University of Iowa Children’s Hospital who had CIEDs. Data transmitted by RM were analyzed. The following data were examined: patient demographics; median interval between transmissions; detection of adverse events requiring corrective measures, including detection of lead failure; detection of arrhythmias and device malfunctions independent of symptoms; time gained in the detection of events using RM versus standard practice; the validity of RM; and the impact of RM on data management. Of 198 patients, 162 submitted 615 RM transmissions. The median time between remote transmissions was 91 days. Of 615 total transmissions, 16 % had true adverse events with 11 % prompting clinical intervention. Of those events requiring clinical response, 61 % of patients reported symptoms. The median interval between last follow-up and occurrence of events detected by RM was 46 days, representing a gain of 134 days for patients followed-up at 6-month intervals and 44 days for patients followed-up at 3 month-intervals. The sensitivity and specificity of RM were found to be 99 and 72 %, respectively. The positive and negative predictive values were found to be 41 and 99 %, respectively. RM allows for early identification of arrhythmias and device malfunctions, thus prompting earlier corrective measures and improving care and safety in pediatric patients.
doi:10.1007/s00246-013-0774-5
PMCID: PMC3897867  PMID: 23949666
Remote monitoring; Pediatrics; Implantable cardiac devices; Home monitoring; Telemedicine; Remote follow-up
18.  The Importance of Wnt Signaling in Cardiovascular Development 
Pediatric cardiology  2009;31(3):342-348.
Cardiac development is comprised of a series of morphological events tightly controlled both spatially and temporally. The molecular pathways controlling early cardiac differentiation are poorly understood, but Wnt signaling is emerging as a critical pathway for multiple aspects of early cardiovascular development. The Wnt pathway plays multiple roles in regulating cellular behavior including proliferation, differentiation, cell migration, and cell polarity. Recent data have demonstrated that Wnt activity is important for early precardiac mesoderm differentiation but must be inhibited in subsequent steps for cardiomyocyte differentiation to proceed. Given the important role that Wnt signaling plays in both the differentiation of cardiomyocytes from pluripotential stem cells and tissue regeneration in general, an increased understanding of this pathway is likely to enhance our knowledge about both cardiovascular development and reparative mechanisms.
doi:10.1007/s00246-009-9606-z
PMCID: PMC3736804  PMID: 19967349
Cardiac development; Progenitor; Wnt
19.  Ontogeny of cardiac sympathetic innervation and its implications for cardiac disease 
Pediatric Cardiology  2012;33(6):923-928.
The vertebrate heart is innervated by the sympathetic and parasympathetic components of the peripheral autonomic nervous system, which regulates its contractile rate and force. Understanding the mechanisms controlling sympathetic neuronal growth, differentiation, and innervation of the heart may provide insight into the etiology of cardiac arrhythmogenesis. In this review, we provide an overview of the cell signaling pathways and transcriptional effectors that regulate both the noradrenergic gene program during sympathetic neurogenesis and regional nerve density during cardiac innervation. We detail recent studies exploring transcriptional regulation of the bHLH transcription factor Hand1 in developing sympathetic neurons, and discuss how the Hand1 sympathetic neuron-specific cis-regulatory element may be further utilized to assess the contribution of altered sympathetic innervation to human cardiac disease.
doi:10.1007/s00246-012-0248-1
PMCID: PMC3391355  PMID: 22395650
sympathetic nervous system; neural crest
20.  Cardiac Sodium Channel Nav1.5 Mutations and Cardiac Arrhythmia 
Pediatric Cardiology  2012;33(6):943-949.
As a major cardiac voltage-gated sodium channel isoform in the heart, Nav1.5 channel is essential for the cardiac action potential initiation and the subsequent propagation throughout the heart. Mutations of Nav1.5 have been linked to a variety of cardiac disease such as long QT syndrome (LQTs), Brugada syndrome, cardiac conduction defect, atrial fibrillation and dilated cardiomyopathy. Mutagenesis approach and heterologous expression systems are most frequently used to study the function of this channel. This review is primarily focused on recent findings on Nav1.5 mutations that are associated with type 3 long QT syndrome (LQT3) in particular. Understanding the functional changes of the Nav1.5 mutation may offer critical insight into the mechanism of long QT3 syndrome. In addition, this review will provide the updated information on the current progress of using various experimental model systems to study primarily the long QT3 syndrome.
doi:10.1007/s00246-012-0303-y
PMCID: PMC3393812  PMID: 22460359
Cardiac sodium channel; cardiac arrhythmia; sodium channel mutation
21.  Calsequestrin Mutations and Catecholaminergic Polymorphic Ventricular Tachycardia 
Pediatric Cardiology  2012;33(6):959-967.
Cardiac calsequestrin (Casq2) is the major Ca2+ binding protein in the sarcoplasmic reticulum which is the principle Ca2+ storage organelle of cardiac muscle. Over the last decade, experimental studies have provided new concepts on the role of Casq2 in the regulation of cardiac muscle Ca2+ handling. Furthermore, mutations in the gene encoding for cardiac calsequestrin, CASQ2, cause a rare but severe form of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations. We also describe the clinical aspects of CPVT and provide an update of its contemporary clinical management.
doi:10.1007/s00246-012-0256-1
PMCID: PMC3393815  PMID: 22421959
22.  The Role of FK506-Binding Proteins 12 and 12.6 in Regulating Cardiac Function 
Pediatric cardiology  2012;33(6):988-994.
Specifically, FK506-binding proteins 12 (FKBP12) and 12.6 (FKBP12.6) are cis–trans peptidyl prolyl isomerases that are expressed in the heart. Both FKBP12 and FKBP12.6 were previously known to interact with ryanodine receptors in striated muscles. Although FKBP12 is abundantly present in the heart, its function in the heart is largely uncertain. Recently, by generating FKBP12 transgenic overexpression and cardiac-restricted knockout mice, we showed that FKBP12 is critically important in regulating trans-sarcolemmal ionic currents, predominately the voltage-gated Na+ current, INa, but it appears to be less important for regulating cardiac ryanodine receptor function. Similar genetic approaches also confirm the role of FKBP12.6 in regulating cardiac ryanodine receptors. The current study demonstrated that FKBP12 and FKBP12.6 have very different physiologic functions in the heart.
doi:10.1007/s00246-012-0298-4
PMCID: PMC3582179  PMID: 22460357
FK506-binding protein; Cardiac function; Arrhythmia; Voltage-gated sodium channel; Ryanodine receptor; Calcium release
23.  Imaging Arrhythmogenic Calcium Signaling in Intact Hearts 
Pediatric cardiology  2012;33(6):968-974.
Protein complex of the cardiac junctional sarcoplasmic reticulum (SR) membrane formed by type 2 ryanodine receptor, junction, triadin, and calsequestrin is responsible for controlling SR calcium (Ca) release. Increased intracellular calcium (Cai) activates the electrogenic sodium–Ca exchanger current, which is known to be important in afterdepolarization and triggered activities (TAs). Using optical-mapping techniques, it is possible to simultaneously map membrane potential (Vm) and Cai transient in Langendorff-perfused rabbit ventricles to better define the mechanisms by which Vm and Cai interactions cause early afterdepolarizations (EADs). Phase 3 EAD is dependent on heterogeneously prolonged action potential duration (APD). Electrotonic currents that flow between a persistently depolarized region and its recovered neighbors underlies the mechanisms of phase 3 EADs and TAs. In contrast, “late phase-3 EAD” is induced by APD shortening, not APD prolongation. In failing ventricles, upregulation of apamin-sensitive Ca-activated potassium (K) channels (IKAS) causes APD shortening after fibrillation-defibrillation episodes. Shortened APD in the presence of large Cai transients generates late-phase 3 EADs and recurrent spontaneous ventricular fibrillation. The latter findings suggest that IKAS may be a novel antiarrhythmic targets in patients with heart failure and electrical storms.
doi:10.1007/s00246-012-0236-5
PMCID: PMC3586331  PMID: 22349681
Triggered activity; After depolarization; Ventricular fibrillation; Calcium dynamics; Optical mapping
24.  Functional screening of intracardiac cell transplants using two-photon fluorescence microscopy 
Pediatric cardiology  2012;33(6):929-937.
Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, its intrinsic renewal rate is insufficient to compensate for myocyte loss during cardiac disease. Transplantation of donor cardiomyocytes or cardiomyogenic stem cells is considered a promising strategy to reconstitute cardiac mass, provided the engrafted cells functionally integrate with host myocardium and actively contribute to its contractile force. We have previously developed a two-photon fluorescence microscopy-based assay that allows in situ screening of donor cell function following their intracardiac delivery. Here we review the techniques and summarize its application for quantitation of the extent to which a variety of donor cell types stably and functionally couple with the recipient myocardium.
doi:10.1007/s00246-012-0314-8
PMCID: PMC3595013  PMID: 22481568
Cellular transplantation; myocardial regeneration; intracellular calcium regulation; two-photon fluorescence microscopy
25.  Incidence and Management of Life-Threatening Adverse Events During Cardiac Catheterization for Congenital Heart Disease 
Pediatric Cardiology  2013;35:140-148.
Continued advancements in congenital cardiac catheterization and interventions have resulted in increased patient and procedural complexity. Anticipation of life-threatening events and required rescue measures is a critical component to preprocedural preparation. We sought to determine the incidence and nature of life-threatening adverse events in congenital and pediatric cardiac catheterization, risk factors, and resources necessary to anticipate and manage events. Data from 8905 cases performed at the 8 participating institutions of the Congenital Cardiac Catheterization Project on Outcomes were captured between 2007 and 2010 [median 1,095/site (range 133–3,802)]. The incidence of all life-threatening events was 2.1 % [95 % confidence interval (CI) 1.8–2.4 %], whereas mortality was 0.28 % (95 % CI 0.18–0.41 %). Fifty-seven life-threatening events required cardiopulmonary resuscitation, whereas 9 % required extracorporeal membrane oxygenation. Use of a risk adjustment model showed that age <1 year [odd ratio (OR) 1.9, 95 % CI 1.4–2.7, p < 0.001], hemodynamic vulnerability (OR 1.6, 95 % CI 1.1–2.3, p < 0.01), and procedure risk (category 3: OR 2.3, 95 % CI 1.3–4.1; category 4: OR 4.2, 95 % CI 2.4–7.4) were predictors of life-threatening events. Using this model, standardized life-threatening event ratios were calculated, thus showing that one institution had a life-threatening event rate greater than expected. Congenital cardiac catheterization and intervention can be performed safely with a low rate of life-threatening events and mortality; preprocedural evaluation of risk may optimize preparation of emergency rescue and bailout procedures. Risk predictors (age < 1, hemodynamic vulnerability, and procedure risk category) can enhance preprocedural patient risk stratification and planning.
Electronic supplementary material
The online version of this article (doi:10.1007/s00246-013-0752-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00246-013-0752-y
PMCID: PMC3882522  PMID: 23900744
Cardiac catheterization and intervention; Mortality; ECMO; Cardiac surgery; Congenital heart disease

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