Piers Barker

Enalapril in Infants With Single Ventricle Results of a Multicenter Randomized Trial

Background— Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown. Methods and Results— The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg · kg−1 · d−1) or placebo who were followed up until 14 months of age. The primary end point was weight-for-age z score at 14 months. The primary analysis was intention to treat. A total of 185 infants completed the study. There were 24 and 21 withdrawals or deaths in the enalapril and placebo groups, respectively (P=0.74). Weight-for-age z score was not different between the enalapril and placebo groups (mean±SE −0.62±0.13 versus −0.42±0.13, P=0.28). There were no significant group differences in height-for-age z score, Ross heart failure class, brain natriuretic peptide concentration, Bayley scores of infant development, or ventricular ejection fraction. The incidence of death or transplantation was 13% and did not differ between groups. Serious adverse events occurred in 88 patients in the enalapril group and 87 in the placebo group. Conclusions— Administration of enalapril to infants with single-ventricle physiology in the first year of life did not improve somatic growth, ventricular function, or heart failure severity. The results of this randomized trial do not support the routine use of enalapril in this population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

Targeted Neonatal Echocardiography in the Neonatal Intensive Care Unit: Practice Guidelines and Recommendations for Training Writing group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC)

Luc Mertens, MD, PhD, FASE, FESC, Istvan Seri, MD, PhD, HonD, Jan Marek, MD, PhD, FESC, Romaine Arlettaz, MD, Piers Barker, MD, FASE, Patrick McNamara, MD, MB, FRCPC, Anita J. Moon-Grady, MD, Patrick D. Coon, RDCS, FASE, Shahab Noori, MD, RDCS, John Simpson, MD, FRCP, FESC, Wyman W. Lai, MD, MPH, FASE, Toronto, Ontario, Canada; Los Angeles and San Francisco, California; London, United Kingdom; Zurich, Switzerland; Durham, North Carolina; Philadelphia, Pennsylvania; New York, New York

Targeted Neonatal Echocardiography in the Neonatal Intensive Care Unit: Practice Guidelines and Recommendations for Training

AAP : American Academy of Pediatrics AEPC : Association for European Paediatric Cardiology ASE : American Society of Echocardiography CDH : Congenital diaphragmatic hernia CHD : Congenital heart disease EAE : European Association of Echocardiography ECMO : Extracorporeal membrane oxygenation EF : Ejection fraction LV : Left ventricular MPI : Myocardial performance index mVCFc : Mean velocity of circumferential fiber shortening NICU : Neonatal intensive care unit PA : Pulmonary artery PDA : Patent ductus arteriosus RA : Right atrial RV : Right ventricular RVSp : Right ventricular systolic pressure SF : Shortening fraction SVC : Superior vena cava TEE : Transesophageal echocardiography TNE : Targeted neonatal echocardiography TVI : Time-velocity integral 2D : Two-dimensional VLBW : Very low birth weight The role of echocardiography in the neonatal intensive care unit (NICU) has changed over the past few years. Previously, nearly all echocardiographic studies in the NICU were performed by pediatric cardiologists to diagnose or monitor congenital heart disease (CHD) and to screen for patent ductus arteriosus (PDA). More recently, neonatologists have become interested in the echocardiographic assessment of hemodynamic instability in infants. The terms functional echocardiography and point-of-care echocardiography have been introduced to describe the use of echocardiography as an adjunct in the clinical assessment of the hemodynamic status in neonates.1–4 The increasing availability of echocardiography, with miniaturization of the technology, has resulted in more widespread use of echocardiography in NICUs around the world.5 Perhaps the most significant challenge for the application of so-called functional studies is that newborns in the NICU with hemodynamic instability are at a much higher risk for having underlying CHD. In addition, newborns in the NICU are unique in that they are in the process of …

Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy

A trial to evaluate the safety and immunogenicity of recombinant modified vaccinia Ankara (MVA) and fowlpox (FP) vectors expressing multiple HIV-1 proteins was conducted in twenty HIV-1 infected youth with suppressed viral replication on HAART. The MVA and FP-based multigene HIV-1 vaccines were safe and well tolerated. Increased frequencies of HIV-1 specific CD4+ proliferative responses and cytokine secreting cells were detected following immunization. Increased frequencies and breadth of HIV-1 specific CD8 T-cell responses were also detected. Plasma HIV-1-specific antibody levels and neutralizing activity were unchanged following vaccination. Poxvirus-based vaccines may merit further study in therapeutic vaccine protocols.

Predictors of Disease Progression in Pediatric Dilated Cardiomyopathy

Background—Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM. Methods and Results—The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using Cox proportional hazards modeling and classification and regression tree analysis. Of the 127 patients, 28 (22%) had disease progression during the 18-month follow-up. Multivariable analysis identified older age at diagnosis (hazard ratio=1.14 per year; P<0.001), larger left ventricular (LV) end-diastolic M-mode dimension z-score (hazard ratio=1.49; P<0.001), and lower septal peak systolic tissue Doppler velocity z-score (hazard ratio=0.81; P=0.01) as independent predictors of disease progression. Classification and regression tree analysis stratified patients at risk of disease progression with 89% sensitivity and 94% specificity based on LV end-diastolic M-mode dimension z-score ≥7.7, LV ejection fraction <39%, LV inflow propagation velocity (color M-mode) z-score <−0.28, and age at diagnosis ≥8.5 months. Conclusions—In children with chronic stable DCM, a combination of diagnosis after late infancy and echocardiographic parameters of larger LV size and systolic and diastolic function predicted disease progression. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Right Ventricular Mechanics using a Novel Comprehensive Three-View Echocardiographic Strain Analysis in a Normal Population

BACKGROUND Although quantitative right ventricular (RV) strain analysis may be useful in congenital and acquired heart disease populations with RV failure, a comprehensive, standardized approach is lacking. An 18-segment RV strain analysis obtained from three standardized RV apical echocardiographic images was used to determine the feasibility, normal values, and reproducibility of the method in normal adults. METHODS Forty healthy, prospectively enrolled volunteers with no cardiac histories and normal QRS durations underwent echocardiography optimized for strain analysis including three RV apical views. Two-dimensional speckle-tracking longitudinal strain analysis was performed using EchoPAC software. Eleven retrospectively identified subjects with RV disease were included as a pilot population. All had been imaged using the same protocol including the three RV apical views. RESULTS All control subjects had normal anatomic morphology and function by echocardiography. Feasibility of the RV strain analysis was good (adequate tracking in 696 of 720 segments [97%]). RV global peak systolic strain was -23 ± 2%. Peak strain was highest in the RV free wall and lowest in the septum. Dyssynchrony indices demonstrated no dyssynchrony using left ventricular criteria. Reproducibility of most strain measures was acceptable. This methodology identified important disease not seen in the four-chamber apical view alone in the pilot population of 11 patients with RV disease. Strain patterns and values were different from those in the control population, indicating that differences do exist from normal. CONCLUSIONS Eighteen-segment RV strain analysis is feasible, with strain measures falling into discrete ranges in this normal population. Those with RV disease illustrate the potential utility of this approach. These data indicate that this model can be used for more detailed studies evaluating abnormal RV populations, in which its full potential can be assessed.

Assessment of Quality of Life in Young Patients with Single Ventricle after the Fontan Operation

OBJECTIVES To assess self-reported quality of life (QOL) in a large multicenter cohort of adolescent and young adults surviving Fontan. STUDY DESIGN Cross-sectional. The Pediatric Quality of Life Inventory (PedsQL) was administered to 408 survivors of Fontan ages 13-25 years enrolled in the Pediatric Heart Network Fontan Follow-up Study. Subjects also completed either the Child Health Questionnaire (age <19 years) or Short Form Health Survey (age ≥ 19 years). PedsQL data were compared with matched controls without a chronic health condition. Correlations between the measures were examined. RESULTS Mean PedsQL scores for subjects receiving Fontan were significantly lower than those for the control group for physical and psychosocial QOL (P < .001). Overall, 45% of subjects receiving Fontan had scores in the clinically significant impaired range for physical QOL with 30% in the impaired range for psychosocial QOL. For each 1 year increase in age, the physical functioning score decreased by an average of 0.76 points (P = .004) and the emotional functioning score decreased by an average of 0.64 points (P = .03). Among subjects ≥19 years of age, the physical functioning score decreased by an average of 2 points for each year increase in age (P = .02). PedsQL scale scores were significantly correlated with conceptually related Child Health Questionnaire (P < .001) and Short Form Health Survey scores (P < .001). CONCLUSIONS Survivors of Fontan are at risk for significantly impaired QOL which may decline with advancing age. Routine assessment of QOL is essential to inform interventions to improve health outcomes. The PedsQL allowed QOL assessment from pediatrics to young adulthood. TRIAL REGISTRATION ClinicalTrials.gov: NCT00132782.

Arrhythmias in patients with hypoplastic left heart syndrome.

BACKGROUND Mortality between stage I and II palliation for hypoplastic left heart syndrome (HLHS) has been associated with arrhythmias. The stage-related proportion, associations, and clinical impact of arrhythmias in patients with HLHS have not been evaluated. In addition, arrhythmia subtypes have not been described in this patient group. METHODS We performed a retrospective analysis of all patients at Duke University Medical Center who received one or more palliative stages for HLHS from September 2000 to October 2008. RESULTS Overall, 49 (57%) of 86 patients had 63 arrhythmias. The majority of arrhythmias occurred between stage I and II, with 44 (51%) of 86 patients manifesting a new arrhythmia. Arrhythmias occurring in this interval tended to be associated with a higher mortality compared with arrhythmias occurring after stage II (odds ratio = 3.2 [95% CI 0.84-12.0], P = .09). Overall mortality was similar in patients with and without arrhythmias (P = .99). Supraventricular tachycardia was the most common arrhythmia (16/63; 25%), but persistent bradycardias (sinus node dysfunction or high-grade atrioventricular block) had the worst clinical outcome with 73% mortality (8/11). There was no association between arrhythmia occurrence and degree of tricuspid regurgitation, left ventricular hypertension, genetic syndrome, type of stage I operation, or need for extracorporeal membrane oxygenation. CONCLUSIONS A large proportion of patients with HLHS experience serious arrhythmias requiring therapy, especially between stage I and II. Persistent bradycardia following stage I is associated with a high mortality rate. Considering all arrhythmia patients, overall mortality was not different compared with the arrhythmia-free group.

Use of cardiac magnetic resonance imaging to evaluate cardiac structure, function and fibrosis in children with infantile Pompe disease on enzyme replacement therapy.

BACKGROUND Pompe disease (acid α-glucosidase deficiency) is one of several lysosomal storage diseases amenable to treatment with enzyme replacement therapy (ERT). While echocardiography (echo) has been the standard method to evaluate the cardiac response to ERT, cardiac magnetic resonance imaging (CMR) has the advantage of a better tissue definition and characterization of myocardial fibrosis. However, CMR for Pompe disease is not frequently performed due to a high risk of sedation. We report the first use of CMR in a feasible protocol to quantify left ventricular (LV) mass, function, and the presence of myocardial fibrosis in the Pompe population. METHODS Children with Pompe disease on ERT were assessed with transthoracic echo and CMR over a 3 year period at a single institution. Echocardiography was performed using standard techniques without sedation. CMR was performed using retrospectively gated and real-time imaging, with and without sedation. LV mass indexed to body surface area (LVMI) and ejection fraction (EF) were measured by both echo and CMR, and evaluated for change over time. Myocardial fibrosis was assessed by CMR with delayed enhancement imaging 5-10 min after gadolinium contrast using single shot inversion recovery sequences with inversion time set to null the signal from normal myocardium. RESULTS Seventeen CMR scans were successfully performed in 10 subjects with Pompe disease (median age at first CMR is 9 months, range 1-38 months, 80% male), with sedation only performed in 4 studies. There was a median interval of 5 months (range 0-34 months) from the start of ERT to first CMR (baseline). At baseline, the median indexed LVMI by CMR (140.0 g/m(2), range 43.8-334.0) tended to be lower than that assessed by echo (median 204.0 g/m(2), range 52.0-385.0), but did not reach statistical significance. At baseline, CMR EF was similar to that assessed by echo (55% vs. 55%). Overall, there was no significant decrease in CMR measured LVMI over time (CMR median LVMI at baseline 94 g/m(2) (range 43.8-334) vs. CMR median at most recent study 44.5 g/m(2) (range 34-303), p=0.44). In 5 patients with serial CMR scans over time, LVMI decreased in 2, was similar in 2, and increased in 1 patient with high sustained antibodies to exogenous enzyme. Delayed enhancement was noted in only l separate patient who also had high sustained antibodies to exogenous enzyme. CONCLUSION CMR is an imaging tool that is feasible to use to serially follow LVMI and EF in children with Pompe disease on ERT. Real-time imaging is adequate for quantification purposes in these patients and minimizes the need for sedation. Quantitative CMR LVMI is generally lower than echo derived LVMI. Delayed enhancement appears to be a rare finding by CMR in Pompe disease. A further follow-up is necessary to better understand the long term effects of ERT in infantile Pompe survivors, especially those with high sustained antibody titers or advanced cardiac disease at treatment outset.

Sildenafil Exposure and Hemodynamic Effect after Fontan Surgery

Objective: Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery. Design: Prospective dose-escalation trial. Setting: Single-center pediatric catheterization laboratory. Patients: Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: median (range) age and weight, 5.2 years (2.5–9.4 yr) and 16.3 kg (9.5–28.1 kg). Five children (55%) were boys, and six of nine (67%) had a systemic right ventricle. Interventions: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 min). Measurements and Main Results: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type-5 inhibition in eight of nine children and 90% inhibition in seven of seven children with doses more than or equal to 0.35 mg/kg. Sildenafil improved stroke volume (+22%, p = 0.05) and cardiac output (+10%, p = 0.01) with no significant change in heart rate in eight of nine children. Sildenafil also lowered systemic (–16%, p = 0.01) and pulmonary vascular resistance index in all nine children (median baseline pulmonary vascular resistance index 2.4 [range, 1.3–3.7]; decreased to 1.9 [0.8–2.7] Wood Units × m2; p = 0.01) with no dose-response effect. Pulmonary arterial pressures decreased (–10%, p = 0.02) and pulmonary blood flow increased (9%, p = 0.02). There was no change in myocardial performance index and no adverse events. Conclusions: After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.