Nancy Halnon

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. METHODS In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. FINDINGS Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1·0 [IQR 0·3-2·2] vs 2·2 [1·3-3·1]; p=0·020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. INTERPRETATION In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. FUNDING BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

Thymic Function and Impaired Maintenance of Peripheral T Cell Populations in Children with Congenital Heart Disease and Surgical Thymectomy

The thymus begins involution in childhood and historically it was thought to be nonfunctional by adulthood, thus presenting no contraindication to the routine practice of thymectomy during cardiothoracic surgery. More recent data suggest, however, that the thymus remains active into adulthood and is responsible for the low-level production of normal T cells. We hypothesize, therefore, that incidental thymectomy during cardiothoracic surgery in infancy causes long-term changes in the cellular immune system. To investigate this hypothesis, we quantified peripheral T-cell subsets and T-cell recombination excision circles in children with congenital heart disease to measure the impact of cardiothoracic surgical procedures and thymectomy performed during a period of immunologic development. We found that cardiothoracic surgical procedures, especially if they include thymectomy, impair T-cell production and produce long-term decreases in total lymphocyte count and CD4+ and CD8+ T-cell subsets, suggesting that long-term maintenance of lymphocyte populations is disturbed.

Immune dysregulation after cardiothoracic surgery and incidental thymectomy: maintenance of regulatory T cells despite impaired thymopoiesis.

Thymectomy is performed in infants during cardiothoracic surgery leaving many patients with reduced thympopoiesis. An association between immune disorders and regulatory T cells (Treg) after incidental thymectomy has not been investigated. Questionnaires soliciting symptoms of atopic or autoimmune disease and biomarkers were measured in children and adults with congenital heart disease and either reduced or preserved thymopoiesis. Tregs were examined. Atopic or autoimmune-like symptoms and elevated anti-dsDNA antibodies were common after surgery in individuals with low thymopoiesis. Total Treg number and function were maintained but with fewer naïve Treg. TCR spectratypes were similar to other memory T cells. These data suggest that thymectomy does not reduce total Treg number but homeostasis is affected with reduced naïve Treg. Prevalence of autoimmune or atopic symptoms after surgery is not associated with total number or proportion of Tregs but appears to be due to otherwise unknown factors that may include altered Treg homeostasis.

Fatal neonatal myocarditis caused by a recombinant human enterovirus-B variant.

We report a case of fatal myocarditis in a newborn infant who was infected with a human enterovirus detected by throat culture and RT-PCR for viral RNA in plasma. Whole genome sequence analysis revealed the virus to be a genomic chimera that likely arose from recombination between coxsackievirus B3 and two recently identified enteroviruses, EV 86 and EV97.

Online Self-Report Data for Duchenne Muscular Dystrophy Confirms Natural History and Can Be Used to Assess for Therapeutic Benefits

To assess the utility of online patient self-report outcomes in a rare disease, we attempted to observe the effects of corticosteroids in delaying age at fulltime wheelchair use in Duchenne muscular dystrophy (DMD) using data from 1,057 males from DuchenneConnect, an online registry. Data collected were compared to prior natural history data in regard to age at diagnosis, mutation spectrum, and age at loss of ambulation. Because registrants reported differences in steroid and other medication usage, as well as age and ambulation status, we could explore these data for correlations with age at loss of ambulation. Using multivariate analysis, current steroid usage was the most significant and largest independent predictor of improved wheelchair-free survival. Thus, these online self-report data were sufficient to retrospectively observe that current steroid use by patients with DMD is associated with a delay in loss of ambulation. Comparing commonly used steroid drugs, deflazacort prolonged ambulation longer than prednisone (median 14 years and 13 years, respectively). Further, use of Vitamin D and Coenzyme Q10, insurance status, and age at diagnosis after 4 years were also significant, but smaller, independent predictors of longer wheelchair-free survival. Nine other common supplements were also individually tested but had lower study power. This study demonstrates the utility of DuchenneConnect data to observe therapeutic differences, and highlights needs for improvement in quality and quantity of patient-report data, which may allow exploration of drug/therapeutic practice combinations impractical to study in clinical trial settings. Further, with the low barrier to participation, we anticipate substantial growth in the dataset in the coming years.

Screening for rejection in symptomatic pediatric heart transplant recipients : The sensitivity of BNP

Abstract:  As the pediatric OHT population expands, there is increasing demand for convenient, yet sensitive screening techniques to identify children with acute rejection when they present to acute care facilities. In children, symptoms of acute rejection or other causes of graft dysfunction are often non‐specific and can mimic other childhood illnesses. The aim of this study was to assess the utility of BNP as a biomarker to assist providers in clinical decision‐making when evaluating symptomatic pediatric heart transplant patients. One hundred twenty‐two urgent care and emergency room visits from 53 symptomatic pediatric OHT patients were retrospectively reviewed to evaluate the relationship between BNP levels, symptoms, and clinical diagnosis at these visits. An ROC curve was generated to determine the accuracy of BNP as a screening tool for acute rejection in this patient population. In this group of patients, a BNP value of >700 pg/mL was 100% sensitive and 92% specific for detecting allograft acute rejection (NPV of 100%). We concluded that BNP is a highly sensitive screening test for acute rejection in symptomatic pediatric heart transplant patients.

The Effect of Gender and Gender Match on Mortality in Pediatric Heart Transplantation

The effect of organ–recipient gender match on pediatric heart transplant mortality is unknown. We analyzed the effects of gender and donor–recipient gender matching. Based on Organ Procurement and Transplant Network data, we performed a historical cohort study in a population of 3630 heart transplant recipients less than 18 years old. We compared unadjusted and adjusted mortality by recipient gender, donor gender and between gender‐matched and gender‐mismatched recipients. Female recipients had decreased survival compared to male recipients (unadjusted hazard ratio [HR] 1.16, confidence interval [CI] 1.02–1.31; p = 0.020). Organ–recipient gender mismatch did not affect mortality for either male or female recipients, though gender‐mismatched females had the worst survival compared to gender‐matched males, who had the best survival (unadjusted HR 1.26, CI 1.07–1.49; p = 0.005). After adjustment for other risk factors affecting transplant mortality, female recipients had decreased survival compared to male recipients (HR 1.27, CI 1.12–1.44; p = 0.020) and gender matching had no effect. In conclusion, gender mismatch alone did not increase long‐term mortality for pediatric heart transplant recipients. However, there may be additive effects of gender and gender matching affecting survival. There are insufficient data at this time to support that recipient and donor gender should affect heart allocation in children.

Development of Quality Metrics in Ambulatory Pediatric Cardiology

The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had attempted to create quality metrics (QM) for ambulatory pediatric practice, but limited evidence made the process difficult. The ACPC sought to develop QMs for ambulatory pediatric cardiology practice. Five areas of interest were identified, and QMs were developed in a 2-step review process. In the first step, an expert panel, using the modified RAND-UCLA methodology, rated each QM for feasibility and validity. The second step sought input from ACPC Section members; final approval was by a vote of the ACPC Council. Work groups proposed a total of 44 QMs. Thirty-one metrics passed the RAND process and, after the open comment period, the ACPC council approved 18 metrics. The project resulted in successful development of QMs in ambulatory pediatric cardiology for a range of ambulatory domains.

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study)

Background Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. Study design This global multi‐center study will use an adaptive, seamless two‐part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52‐week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst‐to‐best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient‐reported HF symptoms will be used to assess efficacy. Conclusion The PANORAMA‐HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. Graphical abstract Design of the two‐stage, seamless, adaptive PANORAMA‐HF study assessing the PK/PD, safety, and efficacy of sacubitril/valsartan versus enalapril in pediatric heart failure patients with systemic left ventricle and reduced left ventricular systolic function. Figure. No Caption available.

Predictors of Memory Deficits in Adolescents and Young Adults with Congenital Heart Disease Compared to Healthy Controls

Introduction Adolescents and young adults with congenital heart disease (CHD) show a range of memory deficits, which can dramatically impact their clinical outcomes and quality of life. However, few studies have identified predictors of these memory changes. The purpose of this investigation was to identify predictors of memory deficits in adolescents and young adults with CHD after surgical palliation compared to healthy controls. Method One hundred fifty-six adolescents and young adults (80 CHD and 76 controls; age 14–21 years) were recruited and administered an instrument to assess memory [Wide Range Assessment of Memory and Learning Second Edition – general memory index (GMI) score] and completed questionnaires that measure anxiety, depression, sleepiness, health status, and self-efficacy. Descriptive and non-parametric statistics were used to assess group differences, and logistic regression to identify predictors of memory deficits. Results CHD subjects consisted of 58% males, median age 17 years, 43% Hispanic, and medians of 2 previous heart surgeries and 14 years since last surgery. Memory deficits (GMI ≤ 85) were identified in 50% CHD compared to 4% healthy controls (median GMI 85 vs. 104, p < 0.001). Of GMI subscale medians, CHD subjects had significantly worse memory performance vs. healthy controls (verbal 88 vs. 105, p < 0.001; attention 88 vs. 109, p < 0.001; working memory 86 vs. 108, p < 0.001). No significant differences appeared between groups for visual memory. Multiple clinical and psychosocial factors were identified which were statistically different on bivariate analyses between the subjects with and without memory deficits. By multivariate analysis, male gender, number of surgeries, anxiety, and self-efficacy emerged as independent predictors of memory deficits. Conclusion Adolescents and young adults with CHD, more than a decade since their last surgery, show significant verbal, attention, and working memory deficits over controls. To enhance patient memory/self-care, clinicians should explore ways to reduce anxiety, improve self-efficacy, and increase use of visual patient education material, especially in CHD males.