Cardiac allograft vasculopathy and graft failure in pediatric heart transplant recipients after rejection with severe hemodynamic compromise.

BACKGROUND: Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC. METHODS: Data from 3,259 heart transplant (HT) recipients between January 2005 and December 2015 in the Pediatric Heart Transplant Study (PHTS) were analyzed. Predictors for RSHC and outcome after RSHC were sought. Time to RSHC was analyzed using the Cox proportional hazards regression model. Cardiac allograft vasculopathy (CAV) after HT and CAV after RSHC were analyzed as time-dependent covariates. Timing of RSHC was analyzed as occurring before and after 4 years after RSHC. RESULTS: There were 309 patients (9.5%) with ≥ 1 RSHC episodes. In 143 patients with RSHC, the first episode was within 1 year after HT. Independent risk factors for RSHC were age 1 to 5 years at HT (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.04-2.18), age > 10 years at HT (HR, 1.83; 95% CI, 1.29-2.60), black race (HR, 1.64; 95% CI, 1.25-2.15), prior cardiac surgery (HR, 1.55; 95% CI, 1.03-2.31), ventricular assist device support at HT (HR, 1.65; 95% CI, 1.18-2.29), maintenance steroids (HR, 1.39; 95% CI, 1.06-1.82), and recipient on inotropes, pressors, or thyroid hormones (HR, 1.45; 95% CI, 1.09-1.94). Graft survival at 5 years after RSHC was 45.7%. RSHC was a greater risk factor for earlier CAV (HR, 7.78; 95% CI, 5.82-10.40) than other rejection types (HR, 2.31; 95% CI, 1.79-3.00). Patients with late RSHC, after 1 year after RSHC had increased risk of graft loss 4 years after RSHC (HR, 7.12; 95% CI, 2.18-23.22). The 5-year graft survival after RSHC was 50.5% for early RSHC and 39.0% for late RSHC. CONCLUSIONS: Mortality after RSHC is high in the current treatment era. Many patient risk factors for RSHC cannot be modified, including age, race, prior cardiac surgery, and ventricular assist device support. After RSHC, CAV is the only predictor of graft failure. Patients who have late RSHC fare worse than those who have RSHC within the first year after HT.

Role of Octreotide in Pediatric Gastrointestinal Bleeding Secondary to Angiodysplasia in Children With Right Heart Failure.

OBJECTIVES: Angiodysplasia (AD) is a relatively uncommon cause of gastrointestinal bleeding in children and may be seen in right heart failure. Octreotide has been used successfully in adult patients with gastrointestinal bleeding due to ADs. METHODS: We describe 2 patients who had congenital heart disease with right heart failure and gastrointestinal bleeding from AD. RESULTS: AD lesions were documented on traditional endoscopy and capsule endoscopy. Bleeding resolved after initiation of IV octreotide and did not recur on subcutaneous octreotide during the 2-year follow-up period. CONCLUSIONS: Based on the successful outcomes in the 2 patients, a trial of octreotide may be considered in pediatric patients who present with gastrointestinal bleeding secondary to AD.

Pulp therapy in pediatric patients with congenital heart disease: survey of American Academy of Pediatric Dentistry members.

PURPOSE: The purpose of this study was to identify treatment options recommended by American Academy of Pediatric Dentistry (AAPD) members concerning pulp treatment in primary teeth in pediatric patients with congenital heart disease (CHD). METHODS: A web-based survey was sent to all active members of the AAPD. The survey contained radiographs of pulpally involved primary teeth, a description of associated signs/symptoms, and a medical history of the patient who was positive for a type of CHD. Pediatric dentists were requested to report treatment recommendations. RESULTS: Of the 6,590 surveys sent, 1,493 surveys (23%) were completed. Most respondents preferred to extract the tooth with the clinical presentation of irreversible pulpitis followed by distal shoe space maintenance when the patient presented with a negative medical history. By contrast, approximately half of the respondents elected to extract this tooth without space maintenance for all of the cardiac conditions. By contrast, most respondents elected to perform a pulpotomy in the case of reversible pulpitis regardless of the medical history. Indirect or direct pulp therapy were the least chosen options for both presentations. CONCLUSIONS: The presence of CHD affects treatment decisions in teeth exhibiting irreversible pulpitis with symptomatic apical periodontitis but not in teeth displaying reversible pulpitis with a normal periodontal status.

The effects of aripiprazole on electrocardiography in children with pervasive developmental disorders.

OBJECTIVES: Psychotropic medications, including the atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated aripiprazole's effects on electrocardiograms, but no pediatric studies have been published to date. METHODS: Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and end point visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QT(c), and RR intervals were recorded. The QT interval was corrected using Bazett's, United States Food and Drug Administration (FDA) Pharmacology Division, and Fridericia's formulas. RESULTS: Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5-17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5-15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No post-treatment QT(c) exceeded 440 ms. CONCLUSIONS: To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.

2011 Riley Heart Center Symposium on cardiac development: development of the cardiac conduction system and arrhythmias.

This article gives an overview of the 2011 Riley Heart Center Symposium that was held in Indianapolis, IN, USA, 11-13 September, 2011.

Does cytomegalovirus serology impact outcome after pediatric heart transplantation?

BACKGROUND: Cytomegalovirus (CMV) infection has been implicated in a number of complications after heart transplantation. A recent study suggested that children with positive CMV serology (CMV(+)) before transplantation are at increased risk of developing coronary allograft vasculopathy (CAV) and death when compared with CMV(-) recipients. We analyzed data from the Pediatric Heart Transplant Study Group to determine the impact of recipient CMV status and CMV mismatching on outcome. In addition, the use and efficacy of CMV prophylaxis were studied. METHODS: Subjects <18 years of age who underwent heart transplantation during the period from 1993 to 2007 were analyzed. Those transplants in which either the recipient or donor were <6 months of age were excluded due to the confounding effects of maternal antibody. The primary outcome variable was freedom from CAV (mild or greater). Secondary outcomes included freedom from death and freedom from clinical CMV infection. Risk factors were assessed using parametric hazard regression. RESULTS: Of the 1,598 subjects included in the analysis, 637 (40%) were CMV(+) at the time of transplantation. Some form of CMV prophylaxis was administered to 67% of all recipients, most commonly with a CMV mismatch (donor CMV(+)/recipient CMV(-)). Freedom from clinical CMV infection at 5 years was 91%. Pre-transplant CMV serology was not associated with mortality (p = 0.40) or risk of developing CAV (p = 0.10). CMV mismatch was associated with increased risk of clinical CMV disease (p < 0.001). The use of CMV prophylaxis had no association with mortality or development of CAV. There was also no significant association between CMV prophylaxis and the development of clinical CMV infection. CONCLUSIONS: CMV(+) serology at time of pediatric heart transplantation had no demonstrable association with death or development of CAV. CMV(-) recipients who receive a CMV(+) organ are at increased risk of clinical CMV disease. CMV prophylaxis was commonly used, although further studies are needed to establish an optimal approach for prevention of CMV disease in this population.

Outcome of pediatric patients with dilated cardiomyopathy listed for transplant: a multi-institutional study.

BACKGROUND: The course of dilated cardiomyopathy (DCM) leading to heart failure in children varies; survival with conventional treatment is 64% at 5 years. Heart transplantation (HTx) enables improved survival; however, outcomes from listing for transplant are not well described. This study reports survival of patients with DCM from listing with the availability of mechanical bridge to transplant. METHODS: Patients with a primary diagnosis of DCM (n = 1,098) were identified from a multi-institutional, prospective, registry of patients aged < 18 years listed for HTx from January 1, 1993, to December 31, 2006. RESULTS: Characteristics of DCM patients at listing included a mean age of 7.3 years; 51% male, 64% white ethnicity, 77% United Network for Organ Sharing status I, 66% on inotropic support, 28% mechanically ventilated, and 15% on mechanical support. Waitlist mortality was 11%, and 75% underwent HTx at 2 years after listing. Overall 10-year survival after listing was 72%, with higher risk of death associated with arrhythmias, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) support, but not ventricular assist device (VAD) support. Survival at 10 years post-HTx was 72%, with a higher risk of death associated with black race, older age, mechanical ventilation, longer ischemic time, and earlier era of transplant. CONCLUSIONS: Transplantation for DCM in the pediatric population offers enhanced survival compared with the natural history. Overall waitlist mortality for DCM is low, with the exception of patients on ECMO, mechanically ventilated, or with arrhythmias. DCM patients fared well after transplant, making HTx a key therapeutic intervention.

Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway.

BACKGROUND: Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose). Nontransgenic mice exhibited reduced left ventricular systolic function (predoxorubicin fractional shortening [FS] 61+/-2%, postdoxorubicin FS 45+/-2%, mean+/-SEM, P<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of doxorubicin treatment. In contrast, doxorubicin-treated MHC-CB7 mice exhibited normal left ventricular systolic function (predoxorubicin FS 63+/-2%, postdoxorubicin FS 60+/-2%, P>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated that mTOR (mammalian target of rapamycin) signaling was inhibited in doxorubicin-treated nontransgenic mice but not in doxorubicin-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted, constitutively active mTOR expression (MHC-mTORca) were studied. Left ventricular systolic function (predoxorubicin FS 64+/-2%, postdoxorubicin FS 60+/-3%, P>0.008) and cardiac mass were normal in doxorubicin-treated MHC-mTORca mice, despite levels of cardiomyocyte apoptosis similar to those seen in doxorubicin-treated nontransgenic mice. CONCLUSIONS: These data suggest that doxorubicin treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute doxorubicin cardiotoxicity.

Development of pulmonary hypertension in an infant treated with diazoxide.

Diazoxide is commonly used in the treatment of neonatal hyperinsulinism. We describe a one month-old infant who was treated with diazoxide for prolonged neonatal hyperinsulinism. Shortly after starting diazoxide, she was admitted to the hospital for tachypnea with hypoxemia, and was subsequently diagnosed with laryngomalacia and obstructive apnea. During hospitalization, her clinical course worsened due to the development of severe pulmonary hypertension, presumed due to diazoxide toxicity. Lung biopsy revealed a probable toxic vascular drug reaction. After discontinuing diazoxide, her clinical status improved and eventually returned to baseline.

Value of plasma B-type natriuretic peptide as a marker for rejection in pediatric heart transplant recipients.

We analyzed 211 consecutive plasma B-type natriuretic peptide (BNP) measurements in 59 pediatric heart transplant patients along with echocardiographic and right ventricular endomyocardial biopsy samples. Patients with a biopsy specimen negative for rejection had significantly lower BNP levels than those patients with a biopsy positive (p