Ashwin K. Lal

Successful bridge to transplant with a continuous flow ventricular assist device in a single ventricle patient with an aortopulmonary shunt.

Ventricular assist devices are frequently used to bridge pediatric patients to cardiac transplantation; however, experience in single ventricle patients with aortopulmonary shunts remains limited. This case report addresses the challenge of balancing pulmonary and systemic circulation with a focus on the role of continuous versus pulsatile ventricular assist device support.

Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients

There are limited data available on the bioequivalence of generic and brand‐name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12‐hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy‐confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was −1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.

End-stage renal disease and cardiomyopathy in children: cardiac effects of renal transplantation.

Background. The occurrence and progression of cardiomyopathy is well known in patients with end-stage renal disease (ESRD). However, the feasibility of renal transplantation in the setting of cardiac dysfunction and the effect of renal transplantation on this progression remain poorly studied in pediatric patients. Methods. A single-center, retrospective review of pediatric renal transplants between January 1, 2001, and December 31, 2010, was conducted. Six children with ESRD and severe systolic dysfunction underwent renal transplantation. Clinical data were collected and compared for the pretransplant, peritransplant, and posttransplant periods. Results. Nutritional support, dialysis, and chronic kidney disease and heart failure therapy led to improved cardiac function before transplantation (ejection fraction 28.8%±9.6% vs. 44.4%±11.5%; fractional shortening 12.7%±5.1% vs. 23.6%±6.2%); however, normal systolic function was not achieved before transplantation in any patient. After transplantation, two patients had normalization of systolic function by hospital discharge, while the systolic function of the remaining four patients normalized during the first posttransplant year. Mean ejection fraction 1 year posttransplant was 22 units greater than before transplant. All patients experienced excellent allograft function in the peritransplant period. Mean estimated creatinine clearance 1 year posttransplant was 93.2±33.3 mL/min/1.73 m2. Conclusions. Renal transplantation can be performed safely in children with ESRD and severe systolic dysfunction. After transplantation, systolic function continues to improve and may reach normal levels during the first posttransplant year. The presence of severe systolic dysfunction in pediatric dialysis patients should not deter referral for renal transplantation.

Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey‐based assessment

Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3‐19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (>85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression.

Ventricular assist device use in single ventricle congenital heart disease

As VAD have become an effective therapy for end‐stage heart failure, their application in congenital heart disease has increased. Single ventricle congenital heart disease introduces unique physiologic challenges for VAD use. However, with regard to the mixed clinical results presented within this review, we suggest that patient selection, timing of implant, and center experience are all important contributors to outcome. This review focuses on the published experience of VAD use in single ventricle patients and details physiologic challenges and novel approaches in this growing pediatric and adult population.

When Lightning Strikes Twice in Pediatrics: Case Report and Review of Recurrent Myocarditis

In this article we highlight a unique, illustrative pediatric case of recurrent myocarditis and review the existing literature on the topic. Myocarditis is an important but incompletely understood cause of cardiac dysfunction. Children with fulminant myocarditis often require inotropic or mechanical circulatory support, and researchers in some studies suggest that up to 42% of children who die suddenly have evidence of myocarditis. Recurrent myocarditis is extremely rare, and the vast majority of reported cases involve adult patients. Pediatric providers who suspect a recurrence of myocarditis have limited evidence to guide patient management because the literature in this domain is sparse. Here we present a unique, illustrative pediatric case of recurrent myocarditis. A 14-year-old boy presented for the second time in 2 years with a clinical history strongly suggestive of myocarditis. Although myocarditis was suggested in the results of cardiac MRI, no pathogen was identified during his first presentation. During his second episode of myocarditis, parvovirus was confirmed by polymerase chain reaction testing of an endomyocardial specimen that also met Dallas criteria for myocarditis. With each presentation, he had decreased ventricular function that subsequently normalized. To the best of our knowledge, there are no reports of recurrent myocarditis in children in whom the diagnosis was confirmed by using MRI and/or biopsy data. Reviewing this distinctive case and the existing literature may help characterize this entity and raise awareness among care providers.

Heart failure following the norwood procedure: An analysis of the single ventricle reconstruction trial

BACKGROUND Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure. METHODS We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure. RESULTS Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p < 0.05). CONCLUSIONS By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure.

Development and validation of a major adverse transplant event (MATE) score to predict late graft loss in pediatric heart transplantation

BACKGROUND There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. METHODS Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score. RESULTS Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score. CONCLUSION The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

Tricuspid atresia with progressive ductal restriction in a fetus.

We report a unique case of tricuspid and pulmonary atresia with idiopathic progressive ductus arteriosus restriction in utero. Diligent predelivery planning and a controlled delivery environment led to a favorable outcome.