HomeCirculation: Heart FailureVol. 6, No. 6Circulation: Heart Failure Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation: Heart Failure Editors’ PicksMost Important Articles in Heart Failure in Children Robb D. Kociol, MD Robb D. KociolRobb D. Kociol Search for more papers by this author Originally published1 Nov 2013https://doi.org/10.1161/CIRCHEARTFAILURE.113.000917Circulation: Heart Failure. 2013;6:e73–e79Peak Oxygen Uptake Correlates With Survival Without Clinical Deterioration in Ambulatory Children With Dilated CardiomyopathySummary: In adults, cardiopulmonary exercise testing is an integral part of the decision-making process for heart transplantation listing. However, experience with using cardiopulmonary exercise test as a prognostic tool in children is very limited. In the present study, using cardiopulmonary exercise testing, the authors studied 82 ambulatory children with dilated cardiomyopathy and found that lower peak oxygen uptake was associated with a higher rate of death (without transplantation) and clinical deterioration requiring urgent listing for transplantation. Children with a peak oxygen uptake ≤62% of the predicted value were at particularly high risk. The study provides supportive evidence for the use of cardiopulmonary exercise test for risk stratification of pediatric dilated cardiomyopathy and suggests that exercise test variables may become part of the standard clinical risk assessment of older children with dilated cardiomyopathy.Conclusions: The authors have demonstrated that a cardiopulmonary exercise test is feasible in ambulatory children with dilated cardiomyopathy who are >120 cm height and for the first time have linked peak O2 with outcome in children.1Competing Risks for Death and Cardiac Transplantation in Children With Dilated Cardiomyopathy: Results From the Pediatric Cardiomyopathy RegistrySummary: Prior studies of outcomes for children with dilated cardiomyopathy (DCM) have used a composite end point of death and cardiac transplantation and may have missed identifying predictive factors differentially affecting outcomes, which affect the transplantation listing process. Using competing risk analysis, this study found that at the time of DCM diagnosis, the presence of congestive heart failure, echocardiographic evidence of more severe disease, and increased age at diagnosis predicted worse outcomes, with certain key differences between etiologic groups. For children with idiopathic disease, diagnosis after 6 years of age, congestive heart failure, decreased left ventricular (LV) fractional shortening, increased LV end-diastolic dimension, and decreased height-for-age predicted worse outcomes. Increased LV dilation was predictive of use of transplantation but not of mortality in idiopathic DCM, calling into question the importance of this factor in the decision to list for transplantation. Routine height measurement could highlight those with idiopathic DCM and lower height-for-age z scores who might require more urgent consideration for transplantation listing. For children with neuromuscular disease, decreased LV fractional shortening predicted death or transplantation, whereas increased LV end-diastolic dimension predicted transplantation but not death. For children with myocarditis, older age at diagnosis, congestive heart failure, and increased LV end-diastolic dimension predicted death or transplantation. These results suggest that the etiology of DCM modifies the importance of particular predictive factors. The ability to predict failed medical management may improve if the etiology of the cardiomyopathy can be established earlier. Additionally, analyses of registry data in this manner allow the postulation of predictive algorithms of clinical outcomes.Conclusions: Risk factors for death and transplantation in children varied by DCM etiology. For idiopathic DCM, increased LV end-diastolic dimension was associated with increased transplantation risk but not mortality. Conversely, short stature was significantly related to death but not transplantation. These findings may present an opportunity to improve the transplantation selection algorithm.2Extracorporeal Membrane Oxygenation for Bridge to Heart Transplantation Among Children in the United States: Analysis of Data From the Organ Procurement and Transplant Network and Extracorporeal Life Support Organization RegistrySummary: Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Unfortunately, objective data on the safety and efficacy of ECMO for this purpose are limited in part because ECMO has never been approved by the Food and Drug Administration for this particular indication. In this study, data from the Extracorporeal Life Support Organization and Organ Procurement Transplant Network registries are combined to describe the efficacy and safety profile of ECMO for a bridge to heart transplantation and to propose objective performance goals that can be used as benchmarks to facilitate Food and Drug Administration approval of emerging miniaturized cardiac assist devices intended to replace ECMO. Among 733 children supported with ECMO as a bridge to heart transplantation since the mid-1990s, fewer than half survived to hospital discharge. Most deaths occurred while the children were on the wait list, but children successfully transplanted also had high post-transplantation mortality, accounting for up to one third of all in-hospital deaths. The risk of death was not uniform across all patient groups and varied by cardiac diagnosis, end-organ dysfunction, and duration of ECMO support. In the objective performance goal cohort, patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%), and 1-ventricle congenital heart disease (33%).Conclusions: Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed.3Characterization and Functionality of Cardiac Progenitor Cells in Congenital Heart PatientsSummary: Visionaries in the field of cardiac therapeutics have long looked to a future when damaged hearts could be rebuilt from the cellular level. Reports on bone marrow–derived stem cells and, more recently, endogenous cardiac progenitor cells have focused on their function and utility in rebuilding the hearts of adults. In the pediatric population, the majority of potential clinical applications would involve patients with cardiomyopathy or congenital lesions rather than adulthood ischemic injury. The authors’ study investigated the presence of a resident pool of human cardiac progenitor cells and demonstrated how it changes during postnatal maturation in the nondiseased myocardium of young patients with congenital heart disease. The authors showed that resident human cardiac progenitor cells are present in the young myocardium and are most abundant during the neonatal period. Furthermore, these cells can be isolated from a wide range of congenital heart patients, including neonates and adolescents, as well as those with cyanosis. The authors’ study suggests that the best source of human cardiac progenitor cells is the right atrium, from which small, clinically relevant myocardial specimens can be obtained. These isolated cells can be expanded in vitro and therefore provide a large number of cells for therapeutic applications. The authors’ functional findings with these cells could enhance the development of novel cell-based regenerative approaches not yet explored in congenital heart patients.Conclusions: Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair.4Outcomes of Restrictive Cardiomyopathy in Childhood and the Influence of Phenotype: A Report From the Pediatric Cardiomyopathy RegistrySummary: Restrictive cardiomyopathy is a rare form of cardiomyopathy in childhood with a few risk factors identified for death or transplantation. This analysis from the Pediatric Cardiomyopathy Registry identified 152 cases of restrictive cardiomyopathy among 3375 children with cardiomyopathy (4.5%), approximately one third of whom had a mixed restrictive/hypertrophic phenotype. Survival did not differ between those with pure and mixed phenotypes, but transplant-free survival was inferior in the pure restrictive cardiomyopathy group. Overall outcomes were worse than for all other forms of cardiomyopathy in the Pediatric Cardiomyopathy Registry. Clinical and echocardiographic risk factors at presentation for worse outcome were identified and should aid the clinician in risk stratification.Conclusions: Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival.5Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single VentricleSummary: The Pediatric Heart Network conducted a pharmacogenetic study as part of a multicenter randomized, controlled trial of enalapril versus placebo in single-ventricle infants to assess if renin-angiotensin-aldosterone system (RAAS)–upregulation genotypes influence the response to enalapril. This represents the first pharmacogenetic study of enalapril in a congenital heart disease population. One-hundred fifty-four infants with single ventricle were genotyped and followed up until 14 months of age. Patients with RAAS-upregulation genotypes had persistent increase in ventricular mass and volume despite volume-unloading surgery (ie, superior cavopulmonary connection). Enalapril did not decrease ventricular mass or volume in either genotype group. Patients with high-risk genotypes had lower weight and height at enrollment, and the height impairment persisted in high-risk patients who were receiving enalapril whereas patients receiving placebo normalized their height by 14 months. The high-risk genotype group also showed mild but persistent renal dysfunction. In summary, patients with RAAS-upregulation genotypes failed to show reverse remodeling in response to volume-unloading surgery, had persistent growth abnormalities, especially with enalapril, and had persistent renal dysfunction. These patients may need earlier superior cavopulmonary connection to facilitate reversal of ventricular dilation and hypertrophy before the remodeling becomes irreversible. Because neither enalapril nor surgery showed significant benefit in high-risk genotype patients, there is a need to develop newer therapies in at-risk patients.Conclusions: Renin-angiotensin-aldosterone system–upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to benefit fully from volume-unloading surgery. Follow-up is warranted to assess long-term impact.6Early Predictors of Survival to and After Heart Transplantation in Children With Dilated CardiomyopathySummary: Factors that affect outcome in pediatric heart diseases such as dilated cardiomyopathy are often difficult to define because of the rarity of disease. To study the potential importance of factors at presentation and at listing for heart transplantation in children with dilated cardiomyopathy on outcome, the authors analyzed data from 2 large pediatric registries: the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. In the merged data set, there were 261 children with dilated cardiomyopathy. Among the factors studied were age, duration of illness, sex, race, ventricular geometry, and the clinical or histological diagnosis of myocarditis at presentation. The authors found that death while waiting was associated with ventilator use and older age at listing. A shorter duration of illness was associated with a more urgent listing status (United Network for Organ Sharing status 1). Death after transplantation was associated with black race and lower left ventricular end-diastolic dimension z score at presentation. The authors also found that death after transplantation was associated with the diagnosis of myocarditis at presentation (P<0.009). Death while waiting was not associated with the diagnosis of myocarditis, and 97% of children with myocarditis survived to transplantation. Furthermore, the most common cause of death after transplantation in the myocarditis group was acute rejection (17%). This is the first study to show that children with dilated cardiomyopathy and myocarditis have significantly higher post-transplantation mortality compared with children without myocarditis. This finding suggests that preexisting viral infection or inflammation could adversely affect heart allograft survival and has implications for the management of these children before and after heart transplantation in the future.Conclusions: Mechanical ventilator use and older age at listing predicted death while waiting, whereas nonwhite race, smaller left ventricular dimension, and myocarditis were associated with death after transplantation. Although 97% of children with clinically or biopsy-diagnosed myocarditis at presentation survived to transplantation, they had significantly higher post-transplantation mortality compared with children without myocarditis, raising the possibility that preexisting viral infection or inflammation adversely affects graft survival.7A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial HypertensionSummary: Pulmonary arterial hypertension is an important cause of morbidity and mortality in children and adults. Currently, 8 drugs are approved for adult pulmonary arterial hypertension, yet no drugs are approved for children. Because of similar clinical characteristics and histopathology, treatment for children has been extrapolated from evidence-based adult guidelines. However, better information is required to provide optimal pediatric dosing and to ensure safety in children of all ages. The 16-week, randomized, double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study evaluated the effects of sildenafil in childhood pulmonary arterial hypertension. Treatment-naive children with pulmonary arterial hypertension (n=234; aged 1–17 years; ≥8 kg) received low-, medium-, or high-dose sildenafil or placebo orally 3 times daily. Peak oxygen consumption, measured only in children who were able to perform exercise testing (using cycle ergometry) reliably, was the primary end point. Hemodynamic parameters and World Health Organization functional class were assessed across all patients, including those unable to reliably perform exercise testing.Conclusions: Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PO2 for the 3 sildenafil doses combined was only marginally significant; however, PO2, functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight.8Echocardiographic Predictors of Outcome in Eisenmenger SyndromeSummary: Although echocardiography provides accurate information on cardiac anatomy and physiology, as well as prognosis data in patients with idiopathic pulmonary arterial hypertension, only few data exist on the prognostic power of echocardiographic parameters in adults with Eisenmenger syndrome, which was the subject of this study. The authors’ data from a single center on a large contemporary cohort of adults with Eisenmenger syndrome showed that echocardiographic indices of right ventricular function (tricuspid annular plane systolic excursion, ratio of right ventricular effective systolic to diastolic duration) and right atrial area are predictive of mortality, assessed either alone or even more so in a composite score. Because the assessment of functional class remains difficult, especially in patients with congenital heart disease, the authors think that this score may be used in the risk stratification of Eisenmenger patients and could influence the decision to initiate or escalate therapy.Conclusions: Echocardiographic parameters of right ventricular function and RA area predict mortality in Eisenmenger patients. A new composite echocardiographic score, described herewith, may be incorporated into the noninvasive, periodic assessment of these patients.9Impact of Oral Sildenafil on Exercise Performance in Children and Young Adults After the Fontan Operation: A Randomized, Double-Blind, Placebo-Controlled, Crossover TrialSummary: Children and young adults with functional single-ventricle physiology have decreased exercise capacity as a result of an inability to normally increase transpulmonary blood flow during exercise. A medication capable of decreasing pulmonary vascular resistance might allow improved transpulmonary flow and increased ventricular preload, resulting in improved cardiac output and performance with exercise. In this randomized, double-blind, placebo-controlled, crossover trial, the impact of sildenafil on exercise capacity was examined in a cohort of 28 subjects. The mean age of participants was 14.9 years, and the mean time from the Fontan operation was 11.3 years. In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. In 2 subgroups, those with single left or mixed ventricular morphology and those with a baseline serum brain natriuretic peptide level >100, an improvement in oxygen consumption at the anaerobic threshold was observed in subjects during the sildenafil phase. The findings of this study suggest that sildenafil may be a useful agent to improve exercise performance and activity tolerance in children and young adults with single-ventricle physiology after the Fontan operation. However, the long-term safety and efficacy of sildenafil in this patient population remain unknown.Conclusions: In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. There was also a suggestion of improved oxygen consumption at the anaerobic threshold in 2 subgroups. These findings suggest that sildenafil may be an important agent for improving exercise performance in children and young adults with single-ventricle physiology after the Fontan operation.10Pediatric Pulmonary Hypertension in the Netherlands: Epidemiology and Characterization During the Period 1991 to 2005Summary: In recent years, significant progress has been achieved in understanding the epidemiology and diagnosis of pulmonary hypertension (PH) in adults. In contrast, PH in children remains poorly understood because of a lack of epidemiological and clinical data. This study portrays epidemiological features, including incidence and prevalence, of pediatric PH and especially pulmonary arterial hypertension (PAH) based on nationwide data derived from 2 general medical registries (pediatric cardiology, national hospitalization) in the Netherlands during a 15-year period. This study demonstrates that pediatric PH is characterized by several age-specific diagnoses. More than 80% of these are transient forms of PAH not seen in adults. Progressive PAH in children includes idiopathic PAH (23%) but is mainly associated with congenital heart defects (PAH-CHD; 72%). Annual incidence for all PH diagnoses was 63.7 cases per million children. For iPAH and PAH-CHD, annual incidence and point prevalence averaged 0.7 and 4.4 (iPAH), and 2.2 and 15.6 (PAH-CHD) cases per million children. Incidence of pediatric iPAH was lower than reported in adults, whereas incidence of pediatric PAH-CHD was higher. The group with pediatric PAH-CHD was more heterogeneous with highly variable clinical courses. Survival of Eisenmenger syndrome in children appeared to be worse than that reported in adults. Concomitant syndromes were frequent, especially in progressive PAH (39%). Notably, in the 15-year study period, only 71% of children with a diagnosis of PAH had confirmatory right heart catheterization as required by current guidelines, emphasizing the need for increasing specific clinical expertise. This can be reached by concentrating the care for pediatric PAH in specialized centers.Conclusions: Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower, whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.11Survival in Childhood Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease ManagementSummary: The importance of this study is the size of the cohort for such a rare disease. The Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pediatric cohort is the most comprehensive prospective database of group 1 childhood pulmonary arterial hypertension reported to date. The size of the study (n=216), number of referral sites (n=26), and geographical distribution make the observations generalizable to clinical US practice. Although descriptive, the information is potentially useful for clinicians because it is a mixed incidence and prevalence cohort collected over 3 years. The authors describe the characteristics and outcomes of the cohort, and they identify key predictors of survival in childhood pulmonary arterial hypertension.Conclusions: Using REVEAL, the authors identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes.12Prevalence of Cardiomyopathy in Italian Asymptomatic Children With Electrocardiographic T-Wave Inversion at Preparticipation ScreeningSummary: T-wave inversion (≥2 contiguous leads) on a 12-lead ECG is usually dismissed in children as a normal “juvenile pattern of repolarization.” However, T-wave inversion is a common ECG abnormality of inherited heart muscle diseases such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, which are leading causes of sudden cardiac death in young competitive athletes. These cardiomyopathies are genetically determined and show an age-dependent phenotypic expression. Because early disease manifestations usually occur after puberty, the persistence of T-wave inversion in the postpubertal age raises the problem of differential diagnosis between a developing heart muscle disease and a benign juvenile pattern of repolarization. The present study was designed to assess prospectively the prevalence, age relation, and underlying cardiomyopathy of T-wave inversion in a large, consecutive series of Italian children (2765) with a mean age of 13.9±2.2 years (range, 8–18 years) undergoing preparticipation screening. In this age group, T-wave inversion, localized predominantly in the right precordial leads, was documented in 5.7% of cases, significantly decreased with increasing age and pubertal development, and most important, reflected an underlying cardiomyopathy such as arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy in 2.5% of cases. These results indicate that after complete pubertal development, T-wave inversion becomes significantly less common than traditionally believed, and its persistence may suggest an underlying heart muscle disease at risk of sudden cardiac death. As a corollary, demonstration of postpubertal persistence of T-wave inversion in children engaged in competitive sports activity justifies an echocardiographic investigation, which may lead to presymptomatic identification of early cardiomyopathy.Conclusions: The prevalence of T-wave inversion decreases significantly after puberty. Echocardiographic investigation of children with postpubertal persistence of T-wave inversion at preparticipation screening is warranted because it may lead to presymptomatic diagnosis of a cardiomyopathy that could lead to sudden cardiac death during sports.13Current Outcomes in US Children With Cardiomyopathy Listed for Heart TransplantationSummary: Previous studies have reported worse outcomes in children with nondilated cardiomyopathy (CMP) listed for a heart transplant compared with children with dilated CMP. Because wait-list and post-transplant outcomes in children listed for a heart transplant have improved in recent years, the authors sought to compare these outcomes between children with dilated and nondilated forms of CMP in the current era. They analyzed all children <18 years of age with CMP listed for heart transplant in the United States between July 2004 and December 2010. Of 1436 children analyzed, 83% had dilated and 17% had nondilated form of CMP (167 with restrictive CMP, 72 with hypertrophic CMP). In adjusted analysis, children with nondilated CMP were at higher risk of dying on the wait-list (or becoming too sick to transplant) only if they were on a ventilator support at the time of listing. The risk was similar between the groups among children not on a ventilator support. In children who received a transplant, post-transplant 1-year survival was 94% in children with dilated CMP and 89% in children with nondilated CMP. In adjusted analysis, the risk of post-transplant graft loss was 1.8× in children with nondilated versus those with dilated cardiomyopathy.Conclusions: The increased risk of wait-list mortality in children with nondilated CMP is limited to those on ventilator support at listing. Although the risk of graft loss is modestly higher in children with nondilated forms of CMP, their short-term transplant outcomes are good.14Outcomes of Children Following a First Hospitalization for Dilated CardiomyopathySummary: Dilated cardiomyopathy (DCM) in children is a heterogeneous disease with a variable clinical course. Whereas some patients with DCM can remain relatively clinically stable for several years, others show a more precipitous decline, leading to death or requiring heart transplantation within 1 to 2 years following diagnosis. The authors hypothesized that the first hospitalization for DCM represents an inflection point in a patient’s disease trajectory for which death or the need for cardiac transplantation within 1 year was likely. Furthermore, the authors hypothesized that certain clinical, laboratory, and echocardiographic findings present at the time of first hospital admission were predictive of hospital and 1-year outcomes. The results of this study demonstrate that the first hospitalization for DCM marks a period of high risk for clinical decline, end stage heart failure, and the need for cardiac transplantation when compared with studies of pediatric patients with DCM using time of diagnosis as the study entry point, and that fractional shortening, left ventricular ejection fraction, uric acid, mixed venous saturation, and atrial filling pressures may aid in predicting outcomes. The results of this study may aid practitioners to identify at-risk patients who may benefit from closer outpatient observation, and, perhaps, earlier consideration for cardiac transplantation.Conclusions: The first hospitalization for dilated cardiomyopathy marks a period of high risk for clinical decline, end stage heart failure, and the need for cardiac transplantation. Echocardiographic function and hemodynamic and serum measurements may aid in predicting outcomes. Despite medical management, most patients will be rehospitalized and/or require cardiac transplantation within 1 year of admission.15Conduction Abnormalities in Pediatric Patients With Restrictive CardiomyopathySummary: The findings of this review of pediatric patients with restrictive cardiomyopathy reiterate the high-risk nature of this unique patient population secondary to its association with potential sudden cardiac death. Although tachyarrhythmias will continue to be a major concern in this disease process, the risk of associated life-threatening bradyarrhythmias should not be overlooked. Secondary to the proposed link to central conduction system disease, most notably progressive AV nodal disease, seen in this study, close surveillance with ECG and ambulatory monitoring is warranted. In this study, PR prolongation and a wider QRS complex were associated with an acute cardiac event. The effectiveness of prophylactic pacing in this population as a bridge to cardiac transplantation or potentially as a means to delay listing for cardiac transplantation in patients with preserved pulmonary vascular resistance must be evaluated.Conclusions: Pediatric patients with restrictive cardiomyopathy are at risk for acute high-grade heart block, and, in this cohort, bradycardic events represented a significant portion of all ar
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