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1.  Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy 
European Heart Journal  2012;35(1):33-41.
Although the pathophysiology and treatment of adult heart failure (HF) are well studied, HF in children remains poorly understood. In adults, adrenergic receptor (AR)-mediated adaptation plays a central role in cardiac abnormalities in HF, and these patients respond well to β-blocker (BB) therapy. However, in children with HF, there is a growing body of literature suggesting a lack of efficacy of adult HF therapies. Due to these unanticipated differences in response to therapy and the paucity of data regarding the molecular adaptation of the paediatric heart, we investigated the molecular characteristics of HF in children.
Methods and results
Explanted hearts from adults and children with idiopathic dilated cardiomyopathy and non-failing controls were used in the study. Our results show that the molecular characteristics of paediatric HF are strikingly different from their adult counterparts. These differences include: (i) down-regulation of β1- and β2-AR in children, whereas β2-AR expression is maintained in adults; (ii) up-regulation of connexin43 in children, whereas down-regulation is observed in adults; (iii) no differences in phosphatase expression, whereas up-regulation is observed in adults; (iv) no decrease in the phosphorylation of phospholamban at the Ser16 or Thr17 sites in children, which are known characteristics of adult HF.
There is a different adaptation of β-AR and adrenergic signalling pathways in children with HF compared with adults. Our results begin to address the disparities in cardiovascular research specific to children and suggest that age-related differences in adaptation could influence the response to therapy. These findings could lead to a paradigm shift in the contemporary management of children with HF.
PMCID: PMC3877432  PMID: 22843448
Paediatric dilated cardiomyopathy; β-Adrenergic receptor; CaMK; Phosphatase; Fetal gene programme
2.  Arteriopathy, D-Dimer, and The Risk of Poor Neurologic Outcome in Childhood-Onset Arterial Ischemic Stroke 
The Journal of pediatrics  2012;162(5):1041-6.e1.
To assess whether acute findings of cerebral arteriopathy, large infarct, and acutely elevated plasma D-dimer levels are independently prognostic of poor long-term neurologic outcome as measured at ≥1 year in children with arterial ischemic stroke (AIS).
Study design
Sixty-one patients with childhood-onset (i.e., >28 days of life) AIS were enrolled in a single-institution cohort study at Children’s Hospital Colorado between February 2006 and June 2011. Data on demographic and diagnostic characteristics, antithrombotic treatments, and outcomes were systematically collected.
Cerebral arteriopathy and D-dimer levels >500 ng/mL (a measure of coagulation activation) were identified acutely in 41% and 31% of the cohort, respectively. Anticoagulation was administered in the acute, sub-acute, and chronic periods post-event in 40%, 43%, and 28% of children. When not receiving anticoagulation, patients were routinely treated with aspirin 2–5 mg/kg once-daily for a minimum of one year. Death, major bleeding (including intracranial hemorrhage [ICH]), and recurrent AIS were infrequent. Pediatric Stroke Outcome Measure at one year demonstrated poor outcome in 54%. Acute cerebral arteriopathy and elevated D-dimer were identified as putative prognostic factors for poor outcome; after adjustment for D-dimer, arteriopathy was an independent prognostic indicator (OR=19.0, 95%CI=1.6–229.8; P=0.02).
Arteriopathy and coagulation activation are highly prevalent acutely in childhood AIS. Although recurrent AIS and ICH were infrequent in our cohort, one-half of children experienced a poor neurologic outcome at one year, the risk for which was increased by acute arteriopathy. Substantiation of these findings in multi-institutional cohort studies is warranted, toward prognostic stratification in childhood-onset AIS.
PMCID: PMC4115645  PMID: 23260102
3.  miRNA Expression in Pediatric Failing Human Heart 
miRNAs are short regulatory RNAs that can regulate gene expression through interacting with the 3'UTR of target mRNAs. Although the role of miRNAs has been extensively studied in adult human and animal models of heart disease, nothing is known about their expression in pediatric heart failure patients. Different than adults with heart failure, pediatric patients respond well to phosphodiesterase inhibitor (PDEi) treatment, which is safe in the outpatient setting, results in fewer heart failure emergency department visits, fewer cardiac hospital admissions and improved NYHA classification. We have recently shown that the pediatric heart failure patients display a unique molecular profile that is different from adults with heart failure. In this study we show for the first time that pediatric heart failure patients display a unique miRNA profile, and that expression of some miRNAs correlate with response to PDEi treatment. Moreover, we show that expression of Smad4, a potential target for PDEi-regulated miRNAs, is normalized in PDEi-treated patients. Since miRNAs may be used as therapy for human heart failure, our results underscore the importance of defining the molecular characteristics of pediatric heart failure patients, so age-appropriate therapy can be designed for this population.
PMCID: PMC3694420  PMID: 23333438
microRNA; mRNA; gene regulation; idiopathic dilated cardiomyopathy; phosphodiesterase inhibition; pediatric heart failure
4.  The Hemodynamic Response to Dexmedetomidine Loading Dose in Children With and Without Pulmonary Hypertension 
Anesthesia and analgesia  2013;117(4):10.1213/ANE.0b013e3182a15aa6.
Dexmedetomidine, an α-2 receptor agonist, is widely used in children with cardiac disease. Significant hemodynamic responses, including systemic and pulmonary vasoconstriction, have been reported after dexmedetomidine administration. Our primary goal of this prospective, observational study was to quantify the effects of dexmedetomidine initial loading doses on mean pulmonary artery pressure (PAP) in children with and without pulmonary hypertension.
Subjects were children undergoing cardiac catheterization for either routine surveillance after cardiac transplantation (n = 21) or pulmonary hypertension studies (n = 21). After anesthetic induction with sevoflurane and tracheal intubation, sevoflurane was discontinued and anesthesia was maintained with midazolam 0.1 mg/kg IV (or 0.5 mg/kg orally preoperatively) and remifentanil IV infusion 0.5 to 0.8 μg/kg/min. Ventilation was mechanically controlled to maintain Pco2 35 to 40 mm Hg. When end-tidal sevoflurane was 0% and fraction of inspired oxygen (Fio2) was 0.21, baseline heart rate, mean arterial blood pressure, PAP, right atrial pressure, pulmonary artery occlusion pressure, right ventricular end-diastolic pressure, cardiac output, and arterial blood gases were measured, and indexed systemic vascular resistance, indexed pulmonary vascular resistance, and cardiac index were calculated. Each subject then received a 10-minute infusion of dexmedetomidine of 1 μg/kg, 0.75 μg/kg, or 0.5 μg/kg. Measurements and calculations were repeated at the conclusion of the infusion.
Most hemodynamic responses were similar in children with and without pulmonary hypertension. Heart rate decreased significantly, and mean arterial blood pressure and indexed systemic vascular resistance increased significantly. Cardiac index did not change. A small, statistically significant increase in PAP was observed in transplant patients but not in subjects with pulmonary hypertension. Changes in indexed pulmonary vascular resistance were not significant.
Dexmedetomidine initial loading doses were associated with significant systemic vasoconstriction and hypertension, but a similar response was not observed in the pulmonary vasculature, even in children with pulmonary hypertension. Dexmedetomidine does not appear to be contraindicated in children with pulmonary hypertension.
PMCID: PMC3830564  PMID: 23960035
5.  Prolongation of Cardiac Allograft Survival by a Novel Population of Autologous CD117+ Bone Marrow-Derived Progenitor Cells1 
Autologous CD117+ progenitor cells (PC) have been successfully utilized in myocardial infarction and ischemic injury, potentially through the replacement/repair of damaged vascular endothelium. To date, such cells have not been used to enhance solid organ transplant outcome. In this study, we determined whether autologous bone marrow-derived CD117+PC could benefit cardiac allograft survival, possibly by replacing donor vascular cells. Autologous, positively selected CD117+PC were administered post-transplantation and allografts were assessed for acute rejection. Although significant generation of recipient vascular cell chimerism was not observed, transferred PC disseminated both to the allograft and to peripheral lymphoid tissues and facilitated a significant, dose-dependent prolongation of allograft survival. While CD117+PC dramatically inhibited alloreactive T-cell proliferation in vitro, this property did not differ from non-protective CD117− bone marrow populations. In vivo, CD117+ PC did not significantly inhibit T cell alloreactivity or increase peripheral regulatory T cell numbers. Thus, rather than inhibiting adaptive immunity to the allograft, CD117+ PC may play a cytoprotective role in prolonging graft survival. Importantly, autologous CD117+PC appear to be distinct from bone marrow-derived mesenchymal stem cells (MSC) previously used to prolong allograft survival. As such, autologous CD117+PC represent a novel cellular therapy for promoting allograft survival.
PMCID: PMC3059253  PMID: 21114653
stem cells; transplantation; acute allograft rejection; tolerance induction
6.  Performance of Cavopulmonary Palliation at Elevated Altitude 
Circulation  2008;118(14 Suppl):S177-S181.
Outcomes of patients undergoing cavopulmonary palliation for single ventricle physiology may be impacted by living at altitude, as the passive pulmonary circulation is dependent on the resistance of the pulmonary vascular bed. The objective of this study is to identify risk factors for failure of cavopulmonary palliation at elevated altitude.
Methods and Results
Between January 1995 and March 2007, 122 consecutive patients living at a mean altitude of 1600 m (range 305 to 2570) underwent a bidirectional Glenn (BDG). There was one in-hospital mortality and 7 late deaths. 52 have proceeded to the Fontan procedure. Survival after BDG was 92.4% at 5 years. Freedom from palliation failure, defined as death, transplant, BDG/Fontan takedown, or revision was 81% at 5 years. At a mean follow-up of 39.8 months, 90 patients (75%) were in New York Heart Association class I. Patients with failing cavopulmonary circulation had higher pre-BDG pulmonary artery pressure (PAP) (18.3±6.1 mm Hg versus 14.8±5.1 mm Hg, P=0.016) and higher pre-BDG transpulmonary gradient (TPG) (11.2±6.2 mm Hg versus 7.7±4.3 mm Hg, P=0.014). Post-BDG, patients with palliation failure had increased PAP (15.0±5.7 mm Hg versus 10.8±2.8 mm Hg, P=0.008) and indexed pulmonary vascular resistance (PVRI) (2.43±1.0 Wood U · m2 versus 1.52±0.9 Wood U · m2, P=0.007).
The majority of patients at moderate altitude have favorable outcomes after BDG or Fontan palliation. Risk factors for palliation failure at elevated altitude include PAP >15 mm Hg, TPG >8 mm Hg, and PVRI >2.5 Wood U · m2.
PMCID: PMC3129266  PMID: 18824752
Fontan procedure; single ventricle; altitude
7.  Outcomes of Reparative and Transplantation Strategies for Multilevel Left Heart Obstructions With Mitral Stenosis 
The Annals of thoracic surgery  2008;86(4):1305-1310.
Conventional management for multilevel left heart obstructions and mitral stenosis (Shone’s complex) involves multiple operations that carry additive risks. This study reviews our experience with reconstructive and transplantation approaches for Shone’s complex.
Between 1987 and 2007, 43 patients with mitral stenosis and one or more left-sided obstructions were identified: supramitral ring (n = 13), subaortic stenosis (n = 25), aortic stenosis (n = 24), hypoplastic arch (n = 20), and coarctation (n = 38). Thirty patients underwent a staged reparative approach, including 27 mitral and 51 left ventricular outflow tract operations. Thirteen patients were referred for transplantation. Patients with severe hypoplasia of the left ventricle were excluded.
There was one in-hospital death (2.5%) and six late deaths (14.2%). Actuarial 5- and 10-year survival for staged surgical and transplantation was 88% vs 61.3% and 83.1% vs 61.3% (p = 0.035). At a mean follow-up of 7.9 years, freedom from mitral reoperation was 83.3% and freedom from reoperation for subaortic stenosis was 78.0%. Wait-list mortality was 13.3% (2 of 13). Wait-list time exceeding 90 days was an incremental risk factor for death after transplantation (p = 0.005).
Despite the challenges of a reparative strategy for Shone’s complex, favorable survival and durability outcomes can be expected. Heart transplantation, although avoiding the pitfalls of staged repair, confers increased risks from ongoing physiologic derangements due to uncorrected left heart inflow and outflow obstructions during the wait for donor heart availability.
PMCID: PMC3128450  PMID: 18805182
8.  Outcome of Acute Graft Rejection Associated with Hemodynamic Compromise in Pediatric Heart Transplant Recipients 
Pediatric cardiology  2010;32(1):1-7.
We sought to analyze the outcome of hemodynamically significant acute graft rejection in pediatric heart transplant recipients from a single-center experience. Acute graft rejection remains a major cause of morbidity and mortality for patients who undergo orthotopic heart transplantation and has been associated with the severity of the rejection episode. A retrospective review of all children experiencing a hemodynamically significant rejection episode after orthotopic heart transplantation was performed. Fifty-three patients with 54 grafts had 70 rejection episodes requiring intravenous inotropic support. Forty-one percent of these patients required high-dose inotropic support, with the remaining 59% of patients requiring less inotropic support. Overall graft survival to hospital discharge was 41% for patients in the high-dose group compared to 94% in the low-dose group. Six-month graft survival in patients who required high-dose inotropes remained at 41% compared to 44% in the low-dose group. Hemodynamically significant acute graft rejection in pediatric heart transplant recipients is a devastating problem with poor short- and long-term outcomes. Survival to hospital discharge is dismal in patients who require high-dose inotropic support. In contrast, survival to discharge is quite good in patients who require only low-dose inotropic support; however, six-month graft survival in this group is low secondary to a high incidence of graft failure related to worsening or aggressive transplant coronary artery disease.
PMCID: PMC3120936  PMID: 20963408
Acute graft rejection; Pediatric heart transplant
9.  Outcome of Extracorporeal Membrane Oxygenation for Early Primary Graft Failure After Pediatric Heart Transplantation 
We sought to analyze the indications and outcome of extracorporeal membrane oxygenation (ECMO) for early primary graft failure and determine its impact on long-term graft function and rejection risk.
Early post-operative graft failure requiring ECMO can complicate heart transplantation.
A retrospective review of all children requiring ECMO in the early period after transplantation from 1990 to 2007 was undertaken.
Twenty-eight (9%) of 310 children who underwent transplantation for cardiomyopathy (n = 5) or congenital heart disease (n = 23) required ECMO support. The total ischemic time was significantly longer for ECMO-rescued recipients compared with our overall transplantation population (276 ± 86 min vs. 242 ± 70 min, p < 0.01). The indication for transplantation, for ECMO support, and the timing of cannulation had no impact on survival. Hyperacute rejection was uncommon. Fifteen children were successfully weaned off ECMO and discharged alive (54%). Mean duration of ECMO was 2.8 days for survivors (median 3 days) compared with 4.8 days for nonsurvivors (median 5 days). There was 100% 3-year survival in the ECMO survivor group, with 13 patients (46%) currently alive at a mean follow-up of 8.1 ± 3.8 years. The graft function was preserved (shortening fraction 36 ± 7%), despite an increased number of early rejection episodes (1.7 ± 1.6 vs. 0.7 ± 1.3, overall transplant population, p < 0.05) and hemodynamically comprising rejection episodes (1.3 ± 1.9 vs. 0.7 ± 1.3, overall transplant population, p < 0.05).
Overall survival was 54%, with all patients surviving to at least 3 years after undergoing transplantation. None of the children requiring >4 days of ECMO support survived. Despite an increased number of early and hemodynamically compromising rejections, the long-term graft function is similar to our overall transplantation population.
PMCID: PMC3117294  PMID: 19679252
extracorporeal membrane oxygenation; child; heart transplantation; right-sided heart failure; left-sided heart failure; hypertension pulmonary
10.  Long-Term Outcome of Palliation with Internal Pulmonary Artery Bands After Primary Heart Transplantation for Hypoplastic Left Heart Syndrome 
Pediatric cardiology  2009;30(4):419-425.
The purpose of this study was to describe the long-term outcome of infants with hypoplastic left heart syndrome (HLHS) who underwent placement of internal pulmonary artery bands as part of a transcatheter palliation procedure followed by primary heart transplantation. Transcatheter palliation included stenting of the ductus arteriosus, decompression of the left atrium by atrial septostomy, and internal pulmonary artery band placement. Cardiac hemodynamics, pulmonary artery architecture, and pulmonary artery growth since transplantation are described. Nine infants with HLHS had internal pulmonary artery bands placed and underwent successful heart transplant. No infant required reconstruction of the pulmonary arteries at the time of transplant. At 1 year after transplant, all of the recipients had normal mean pulmonary artery pressure, pulmonary vascular resistance, and transpulmonary gradient. Pulmonary angiography performed at 1 year after transplant demonstrated no distortion of pulmonary artery anatomy with significant interval growth of the branch pulmonary arteries. There was 100% survival to hospital discharge after transplant in this cohort of infants. Transcatheter placement of internal pulmonary artery bands for HLHS offers protection of the pulmonary vascular bed while preserving pulmonary artery architecture and growth with good long-term outcome.
PMCID: PMC3117302  PMID: 19365660
Congenital heart disease; Heart catheterization; Heart transplant; Infant
11.  Cardiac Cell-specific Apoptotic and Cytokine Responses to Reovirus Infection: Determinants of Myocarditic Phenotype 
Journal of cardiac failure  2009;15(6):529-539.
The pathophysiologic mechanisms underlying viral myocarditis are not well defined. As a result, effective treatments do not exist and viral myocarditis remains a potentially lethal infection of the heart.
Methods and Results
We used cultured rat cardiac myocytes and fibroblasts to investigate apoptosis and cytokine production in response to infection by myocarditic vs. non-myocarditic strains of reovirus. Myocarditic reovirus strain 8B and non-myocarditic strain DB188 replicate comparably in each cardiac cell type. However, strain 8B and related myocarditic reoviruses preferentially increase apoptosis of myocytes relative to fibroblasts, whereas DB188 and nonmyocarditic strains preferentially increase fibroblast apoptosis. Infection of cardiac fibroblasts with the nonmyocarditic strain DB188 elicits substantial increases in a panel of cytokines compared to fibroblasts infected with strain 8B or mock-infected controls. Analysis of culture supernatants using cytometric bead arrays revealed that DB188 enhanced release of interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12(p70), GRO-KC, tumor necrosis factor-α, and MCP-1 relative to 8B or mock-infected controls (all P < .05).
We hypothesize that differential cytokine production and cell-specific apoptosis are important determinants of myocarditic potential of reoviral strains. Therapies that target the beneficial effects of cytokines in limiting cytopathic damage may offer an effective and novel treatment approach to viral myocarditis.
PMCID: PMC2772824  PMID: 19643365
Viral myocarditis; myocytes; fibroblasts

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