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Background: Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes., Methods and Results: We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end-diastolic posterior wall thickness, and the LV end-diastolic posterior wall thickness:LVEDD ratio between baseline and follow-up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1-year follow-up had died, received a heart transplant, or were alive and transplant-free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors ( Z score changes of +2.6 and -1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end-diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P =0.004) but was higher in those with progressive LV dilation (HR, 1.45; P <0.001)., Conclusions: Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

Adult studies have shown that depolarization and repolarization abnormalities are associated with worsening heart failure; however, this relationship is not well understood in pediatric congenital heart disease. We evaluated the association between QTc and QRS duration to systolic function and outcome in children with heart failure and reduced ejection fraction (HFrEF). We performed a retrospective, single-center, 14-year cohort study of HFrEF children. Clinical records, echocardiograms, and electrocardiograms were reviewed for every clinical encounter. Diagnosis, interventions, outcomes, QRS and QTc duration, and systolic function were collected. Repeated-measure ANOVA evaluated the association between depolarization and repolarization to cardiac function. Cox regression analysis examined the effects of age, time since diagnosis, and measured and change in QTc and QRS duration on time to transplant/death. We enrolled 136 cardiomyopathy (CM) and 47 structural heart disease (SHD) patients. Prolonged QRS (p = 0.0001) and QTc (p = 0.02) were associated with systolic dysfunction. This association was significant in SHD group (QRS p < 0.0001, QTc p = 0.048), but not CM group (QRS p = 0.5, QTc p = 0.3). Progressive lengthening of QTc was significantly associated with transplant or death in the overall cohort (HR 1.02, CI 1.011-1.028), SHD, (HR 1.020, CI 1.001-1.039), and CM (HR 1.017, CI 1.007-1.027). QTc and QRS prolongation are each associated with ventricular dysfunction in pediatric SHD with heart failure. QTc prolongation is an indication for poor outcomes in SHD and CM groups, leading to a higher risk of death or transplantation. Progressive lengthening of QTc over time in children with HFrEF may indicate increased risk in this population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing ( P =0.005 and P =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

Purpose: Children with cardiomyopathy are at risk of heart failure with reduced physical activity (PA) as a cardinal manifestation. Clinical assessment of PA in children is challenging due to the limited validity of subjective reports. The aim of the study was to compare accelerometery measurement with parental report and to identify factors associated with movement behavior (PA, sedentary time, steps per day)., Method: Fifteen patients with cardiomyopathy (mean, 9.7 years; 64% male) were asked to wear an Actigraph GT3X accelerometer in Edmonton, Canada. Demographics, clinical characteristics, parental-reported PA, and health-related quality of life data were also collected., Results: Participants engaged in a median of 38 minutes of moderate-vigorous PA per day with higher levels in boys versus girls (73.9 [25.03, 78.91] vs 4.13 [2.53, 37.67] minutes, P = .03). Children participating in recreational sports showed a higher level of moderate-vigorous PA (73.92 min/d) compared with those who did not participate (73.9 vs 22.7 min/d, P = .05), and positive family outlook on the child's health was associated with less sedentary time (P = .04)., Conclusion: Accelerometer measurement in children with cardiomyopathy is an achievable and more objective measure of PA compared with parental report alone and highlighted low levels of PA among these children.

Purpose: The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life., Methods: A writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document., Results: A genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted., Conclusion: Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Adverse fibrotic remodeling is detrimental to myocardial health and a reliable method for monitoring the development of fibrotic remodeling may be desirable during the follow-up of patients after heart transplantation (HTx). Quantification of diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) has been increasingly applied and validated histologically in adult patients with heart disease. However, comparisons of CMR findings with histological fibrosis burden in children are lacking. This study aimed to compare native T1 times and extracellular volume fraction (ECV) derived from CMR with the degree of collagen on endomyocardial biopsy (EmBx), and to investigate the association between myocardial fibrosis and clinical as well as functional markers in children after HTx., Methods: EmBx and CMR were performed on the same day. All specimens were stained with picrosirius red. The collagen volume fraction (CVF) was calculated as ratio of stained collagen area to total myocardial area on EmBx. Native T1 values and ECV were measured by CMR on a mid-ventricular short axis slice, using a modified look-locker inversion recovery approach., Results: Twenty patients (9.9 ± 6.2 years of age; 9 girls) after HTx were prospectively enrolled, at a median of 1.3 years (0.02-12.6 years) post HTx, and compared to 24 controls (13.9 ± 2.6 years of age; 12 girls). The mean histological CVF was 10.0 ± 3.4%. Septal native T1 times and ECV were higher in HTx patients compared to controls (1008 ± 32 ms vs 979 ± 24 ms, p < 0.005 and 0.30 ± 0.03 vs 0.22 ± 0.03, p < 0.0001, respectively). CVF showed a moderate correlation with native T1 (r = 0.53, p < 0.05) as well as ECV (r = 0.46, p < 0.05). Native T1 time, but not ECV and CVF, correlated with ischemia time (r = 0.46, p < 0.05)., Conclusions: CMR-derived fibrosis markers correlate with histological degree of fibrosis on EmBx in children after HTx. Further, native T1 times are associated with longer ischemia times.

Cardiomyopathies in children encompass a broad range of diseases, both genetic and acquired, which manifest as a primary cardiac disorder or as a cardiomyopathy secondary to systemic disease. The burden of this group of disorders is substantial, and growing on a global scale. The availability of disease altering treatments is limited, and therefore a focused review on the prevention of cardiomyopathies is justified. In this review, we address the prevention of cardiomyopathy in children by dealing with the root causes of disease at a molecular, clinical and population level. Recent years have yielded promising returns in basic research related to gene-targeted therapy, specific anti-viral therapies and modification of the effects of cardiotoxic drugs. Much work remains to be done in the fields of vaccine development, public health and adoption of available treatments. Effective research in this field will require that diagnostic methods are both refined, and made available more broadly, from imaging to gene testing. Much of our knowledge today is derived from the use of registries, which have successfully catalogued the detailed phenotype of affected patients, and provided long-term longitudinal follow up of affected individuals.

Background: Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children., Methods and Results: According to diagnoses from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups (P = .035). Time to listing for cardiac transplantation significantly differed by phenotype (P < .001), as did time to transplantation (P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval [CI] 0.78-23.3) for HCM, 6.35 (95% CI 1.52-26.6) for DCM, and 5.66 (95% CI 1.04-30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis., Conclusions: LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rationale: Cardiomyopathy is a rare condition in children that is associated with high mortality. Although sleep-disordered breathing is prevalent, its frequency and patterns in children with cardiomyopathy are unknown., Objectives: To evaluate the frequency and patterns of sleep-disordered breathing and their relationship to cardiac function in children with primary cardiomyopathy., Methods: This study comprised a prospective, uncontrolled case series. Children with cardiomyopathy completed a sleep questionnaire, overnight polysomnography, blood pressure monitoring, otolaryngological assessment, and transthoracic echocardiography at the Hospital for Sick Children in Toronto, Canada., Measurements and Main Results: Twenty-one patients (17 males) were recruited. The median age of the patients was 10.7 years, and the median body mass index z score was 0.8. Sleep-disordered breathing was observed in 10 (48%) of 21 patients. Significant central sleep apnea was the main finding in 5 (24%) of 21 of the cohort and in 50% of the sleep-disordered breathing population. The left ventricular end diastolic volume index was greater in children with central sleep apnea than in children without sleep-disordered breathing (P = 0.03). There were significant correlations between the central apnea-hypopnea index and both left ventricular end diastolic and end systolic volume indexes (Spearman's r = 0.55, P = 0.01; Spearman's r = 0.47, P = 0.03, respectively). Snoring, sleep architecture, blood pressure, and otolaryngological findings were not significantly different between children with sleep-disordered breathing versus those without sleep-disordered breathing., Conclusions: Sleep-disordered breathing is common in children with cardiomyopathy. In our present study, 24% of participants exhibited primarily central sleep apnea. The severity of cardiac dysfunction, as measured by left ventricular end diastolic volume index and left ventricular end systolic volume index, is associated with central sleep apnea. Longitudinal research is necessary to better characterize sleep disorders and their impact on cardiac function in a large pediatric cardiomyopathy population.

We report on two families with Sengers syndrome and mutations in the acylglycerol kinase gene (AGK). In the first family, two brothers presented with vascular strokes, lactic acidosis, cardiomyopathy and cataracts, abnormal muscle cell histopathology and mitochondrial function. One proband had very abnormal mitochondria with citrate synthase crystals visible in electron micrographs, associated with markedly high citrate synthase activity. Exome sequencing was used to identify mutations in the AGK gene in the index patient. Targeted sequencing confirmed the same homozygous mutation (c.3G>A, p.M1I) in the brother. The second family had four affected members, of which we examined two. They also presented with similar clinical symptoms, but no strokes. Postmortem heart and skeletal muscle tissues showed low complex I, III and IV activities in the heart, but normal in the muscle. Skin fibroblasts showed elevated lactate/pyruvate ratios and low complex I+III activity. Targeted sequencing led to identification of a homozygous c.979A>T, p.K327* mutation. AGK is located in the mitochondria and phosphorylates monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid. Disruption of these signaling molecules affects the mitochondria's response to superoxide radicals, resulting in oxidative damage to mitochondrial DNA, lipids and proteins, and stimulation of cellular detoxification pathways. High levels of manganese superoxide dismutase protein were detected in all four affected individuals, consistent with increased free radical damage. Phosphatidic acid is also involved in the synthesis of phospholipids and its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue. These two pedigrees confirm that mutation of AGK is responsible for the severe neonatal presentation of Sengers syndrome. The identification of citrate synthase precipitates by electron microscopy and the presence of vascular strokes in two siblings may expand the cellular and clinical phenotype of this disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Abstract: Paediatric cardiomyopathy and heart failure are distinct but frequently associated conditions, which have a high mortality. Traditional medical therapy has evolved to incorporate newer classes of heart failure drugs, although the evidence to support efficacy in children is limited. This perspective article discusses the rationale, benefits and limitations of the various classes of drug therapy used in paediatric heart failure due to cardiomyopathy or congenital heart disease. Controversies in management and challenges for future development are highlighted. [Copyright &y& Elsevier]

Abstract: Biomarkers have established an important role in the diagnosis and prognosis of heart failure in adults, with early indications being that their sensitivity and specificity will be similar in the pediatric population. Since early detection of remodeling is vital to preemptive management in cardiomyopathy and in heart disease arising from congenital lesions, biomarkers may offer a means of identifying high risk patients before they develop symptoms. Although in current use, natriuretic peptides high sensitivity troponins, and C-reactive protein need to have their applications more clearly defined in pediatrics, by evidence based guidelines. Exploratory work should meanwhile continue to define the risk of disease progression in patients with dilated cardiomyopathy, and of sudden death in hypertrophic cardiomyopathy based on biomarker profiles. Further research into the interaction of the genetic basis of disease and proteomic biomarkers will be a valuable means of assessing the importance of different pathways of disease related ventricular remodeling. [Copyright &y& Elsevier]

Abstract: Biomarkers have established an important role in the diagnosis and prognosis of heart failure in adults. Several biomarkers of different classes have also demonstrated a practical or potential role in managing patients with heart failure. In the pediatric population, objective assessment of severity and disease progression is apt to be more difficult. Therefore, biomarkers may represent an objective tool to confirm functional status and echocardiographic indices of left ventricular dysfunction in children with heart failure. Since early detection of remodeling is vital to preemptive management, biomarkers may also serve to gauge the severity of the ventricular remodeling process in several different diseases. Thus far, B-type natriuretic peptide levels have been found to be associated with the severity and outcome of heart failure in children, correlating with symptom severity, functional status and degree of left ventricular remodeling. They have been found to predict cardiovascular events, and may guide medical treatment decisions in symptomatic heart failure. High-sensitivity C reactive protein, cytokines, cytokine receptors, cardiac troponins and gene expression profiling are all emerging as a useful assessment tools in adults with heart failure. Further study is required to validate the role of these measures in children with cardiomyopathies and with heart failure. [Copyright &y& Elsevier]

The article presents information on a study which investigated the extent of difference in left ventricular (LV) recovery between children with myocarditis and idiopathic dilated cardiomyopathy (IDCM). It investigates the difference in mortality, transplantation and echocardiographic normalization of Pediatric Cardiomyopathy Registry (PCMR) patients with a clinical diagnosis of myocarditis validated by endomyocardial biopsy contrasted with the other children diagnosed with myocarditis. It examines the factors that may aid in identifying these outcomes.

Summary: Pediatric cardiomyopathies are a heterogenous group of conditions of which dilated cardiomyopathies are the most common clinicomorphologic subtype. However, the etiology and pathogenesis of many cases of dilated cardiomyopathies remain unknown. We describe a series of 5 cases of a rare but clinically and histologically distinctive dilated cardiomyopathy that was uniformly lethal in early infancy. The 5 cases include 2 pairs of siblings. There was parental consanguinity in 1 of the 2 pairs of siblings. Death occurred in early infancy (range, 22-67 days; mean, 42 days) after a short history of general lethargy, decreased feeding, respiratory distress, or cyanosis. There was no specific birth or early neonatal problems. Autopsy revealed congestive cardiac failure and enlarged, dilated hearts with ventricular dilatation more pronounced than atrial dilatation, and endocardial fibroelastosis. Histology showed prominent hypertrophic nuclear changes of cardiac myofibers and markedly increased myocyte mitotic activity including occasional atypical mitoses. Immunohistochemical staining for Mib1 showed a markedly increased proliferative index of 10% to 20%. Ancillary investigations, including molecular studies, did not reveal a primary cause for the cardiomyopathies. This distinctive dilated cardiomyopathy characterized by unusual histologic features of myocyte nuclear hypertrophy and marked mitotic activity is lethal in early infancy. Its occurrence in 2 pairs of siblings suggests familial inheritance. Although the underlying molecular pathogenesis remains to be elucidated, it is important to recognize this distinctive entity for purposes of genetic counseling. [Copyright &y& Elsevier]

Dilated cardiomyopathy (DC) has been reported in severe epidermolysis bullosa (EB) subtypes. Poor nutritional status, low carnitine levels, selenium deficiency, chronic iron overload, drugs and viral etiology have been proposed as potential contributors. This was a retrospective, descriptive, multicenter study describing EB patients that developed DC, and determining potential pre-disposing risk factors. Fifteen patients were enrolled in the study; 11 of them were male subjects (73%). Eighty-seven per cent of the participants had dystrophic EB and 13% had junctional EB. Mean age at diagnosis of DC was 12.18 ± 4.99 years. Chronic anemia was diagnosed in 13 of 15 patients (86.7%). Sixty per cent of patients had prior red blood cell transfusions. At diagnosis, selenium levels were low in 55% of the patients (n = 11) and total carnitine levels were low in 45% of the patients (n = 11). Systolic function was moderately impaired, with a mean shortening fraction of 19.38% (SD = 5.04, n = 8). After a mean follow-up period of 6.3 ± 4.8 years, six patients were alive without being on any medications (40.0%), two were alive on medications (13.3%) and seven had died (46.7%). Limitations of the study was that it was a retrospective chart review with relatively small sample size. Retrospective chart review, relatively small sample size. This study substantiates the association between DC and EB. Currently, there is no single risk factor identified in EB patients that leads to DC. Further prospective studies are needed. [ABSTRACT FROM AUTHOR]

The current maintenance treatment for children with heart failure remains controversial: To a large extent, it is based on extrapolation of data derived from trials in adult populations. There are only a few randomized trials focused on the treatment of children with cardiac disease, especially in the subgroup with cardiomyopathy and heart failure. The goals of therapy are to maintain circulatory and end-organ function and to allow for recovery and reverse remodeling to occur. When maintenance therapy fails and medical treatment does not result in clinical improvement, the alternative of device therapy must be considered: In that case, the usual aim is to stabilize circulatory status, as a bridge to either recovery or to cardiac transplantation. Recently, carefully selected patients with electromechanical dyssynchrony of ventricular systolic function have demonstrated a benefit from biventricular pacing devices (cardiac resynchronization therapy), with improved functional capacity and quality of life and, in some patients, avoidance of the need for transplantation. [ABSTRACT FROM AUTHOR]

Objectives: We sought to determine whether the introduction of these agents had altered the outcome of dilated cardiomyopathy (DC) in childhood. Background: Pediatric DC has a poor prognosis. Angiotensin-converting enzyme inhibitors (ACEIs) and beta-adrenergic receptor blockers (BBs) improve survival in adults with DC, but their effectiveness in children has not been confirmed. Methods: We performed a single-institution retrospective review of all diagnosed cases of DC and related phenotypic variants between 1976 and 2005, with multivariate analysis of risk factors for the end point of death or cardiac transplantation. Results: A total of 189 patients presented between January 1, 1976, and March 31, 2005. Forty-four patients died, 34 underwent cardiac transplantation, and 10 were lost to follow-up during this period. The 2- and 5-year transplantation-free survival rates for all patients were 63.6% (95% confidence interval [CI]: 56.4% to 70.8%) and 56.3% (95% CI: 48.5% to 64.1%), respectively. For patients treated with digoxin but neither an ACEI nor a BB (n = 51), the 5-year transplantation free survival rate was 67.5% (95% CI: 53.5% to 82.0%) and for those treated with the addition of an ACEI but no BB (n = 65), the rate was 57.2% (95% CI: 43.6% to 69.4%) (p = NS). Combination therapy with an ACEI and a BB (n = 57) was not associated with an improvement in 5-year transplantation-free survival (58.5%; 95% CI: 42.5% to 72.0%, p = NS). In multivariable analysis, presentation with a low left ventricular ejection fraction increased the risk of death or transplantation, but the end point was not influenced by time era or treatment strategy. Conclusions: DC in childhood has a high risk of death or the need for transplantation. Medical treatment has shifted toward combination ACEI and BB therapy in the current era. Our retrospective data, however, suggest only a transient survival advantage associated with the combined use of ACEI and BB over ACEI alone and no obvious or sustained improvement in transplantation-free survival accompanying the change from digoxin-based medical therapy. [Copyright &y& Elsevier]

Current evidence suggests that almost half of all children with cardiomyopathy and symptomatic heart failure will die or require a cardiac transplant within 5 years of diagnosis. The recognition, diagnostic assessment, and treatment of heart failure in children are therefore challenging undertakings, to say the least. It involves an assessment of cardiac appearance and function, adaptation of the child as a whole, and a diagnostic approach that evaluates many possible root causes. This review is intended to assist the practicing pediatrician and cardiologist by providing a framework for this diagnostic assessment and to give an overview of the treatment options available for children with heart failure. In this first part, we will focus on clinical evaluation, diagnostic testing, and initial medical management. In the second part of this series, the maintenance treatment and treatment options applicable when medical treatment is insufficient will be addressed. [ABSTRACT FROM AUTHOR]

Abstract: Heart transplantation is usually utilized in pediatric patients with dilated or restrictive cardiomyopathies, or in patients with hypertrophic cardiomyopathies with the hemodynamic characteristics of dilated or restrictive cardiomyopathies. Pediatric Cardiomyopathy Registry (PCMR) data suggests that transplantation is utilized in patients with idiopathic, familial, or myocarditis dilated cardiomyopathies to a greater extent than in dilated cardiomyopathies observed in malformation syndromes, inborn errors of metabolism or neuromuscular disease. Single and multicenter studies suggest that lower left ventricular ejection fraction at presentation is associated with a greater likelihood and a diagnosis of myocarditis to a decreased likelihood of heart transplantation respectively. International Society for Heart and Lung Transplantation (ISHLT) data demonstrates cardiomyopathy is making up an increasing proportion of heart transplantation in infants. PCMR data suggest that the overall freedom from death or transplantation in patients with pediatric dilated cardiomyopathy has changed little in the past 15 years. However, survival after pediatric heart transplantation has improved over the same time period. Two single center studies have found that while survival with pediatric dilated cardiomyopathy has improved, the freedom from death or transplantation is similar to survival in pediatric dilated cardiomyopathy prior to the routine use of heart transplantation. Furthermore, these studies could find no impact from new medical therapies on transplant-free survival. These findings suggest that heart transplantation may be the most effective therapy for improved survival in pediatric dilated cardiomyopathy. [Copyright &y& Elsevier]

Introduction: Single-gene mutations are a known cause of dilated cardiomyopathy (DCM) in children, but the strength of association between gene-mutations and disease severity is uncertain. Combining exome-sequencing with serial assessment of disease severity may improve our understanding of this genotype-phenotype relationship. Hypothesis: Exome sequencing will identify disease - associated mutations for isolated DCM in children, and mutation carriers will have a more severe phenotype, and a worse clinical outcome than those without identifiable mutations. Methods: A longitudinal cohort study, across 14 pediatric referral centers in North America. Patients aged 0-18 with an echocardiographic diagnosis of DCM provided DNA for exome sequencing. Heart Failure (HF) symptoms, echocardiographic LV dilation and LV ejection fraction (EF) were assessed at presentation, and prospectively for up to 2 years. Endpoints of death or cardiac transplantation were recorded. Results: 279 DCM probands (53% female), median age 1.6 (0.4-10.4) years, were identified between 2012-2016. Median follow up time was 1.1 (0.2-4.0) years. Pathogenic mutations were identified in 19 of 37 genes evaluated, with TTN (17%), TNNT2 (11%), MYH7 (9%), RBM20 (9%) and LMNA (8%) mutations being the most common. While 17.9% of the cohort yielded an identifiable genetic cause, children >12yrs of age had the highest genetic yield, at 33% (p<0.05). Over 39% of patients had no known mutation identified, while 43% had only variants of unknown significance. Symptoms of HF occurred in 63.1% of patients at or within 12 months of presentation, but neither HF symptoms, LVEF nor LV dilation were associated with gene-positive status. Four (1.4 %) patients died and 144 (51.6%) received a heart transplant. Whereas LV dilation, reduced LVEF and HF symptoms were all associated with transplant-free survival (p<0.01), gene-positive status conferred no risk for death or transplant (p=0.4). Conclusions: Pediatric DCM patients with pathogenic mutations in known cardiomyopathy genes do not have more severe disease or increased risk of adverse outcome by 12 months after diagnosis. Further molecular characterization of this disease is required to identify patients at highest risk for deterioration and death. [ABSTRACT FROM AUTHOR]

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10−16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions. [Display omitted] [ABSTRACT FROM AUTHOR]

Background--Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). Methods and Results--We analyzed the Pediatric Cardiomyopathy Registry database (1990-2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively (P=0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P=0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P=0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P<0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. 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. [ABSTRACT FROM AUTHOR]

In adults with idiopathic dilated cardiomyopathy (IDC), mitral regurgitation (MR) is associated with adverse prognosis and is often addressed by surgery or intervention. MR is commonly found in children with IDC, but its prognostic relevance has not been defined, and interventions to reduce MR are not routinely performed in this population. In this study, it was hypothesized that MR is an independent risk factor for death or transplantation. This was a single-center, retrospective study of sequential patients with IDC or familial IDC (left ventricular end-diastolic dimension z score >2 and ejection fraction <50%). Patients with acute myocarditis or previous mitral surgery were excluded. MR severity was graded according to American Society of Echocardiography guidelines as mild, moderate, or severe on the basis of MR jet vena contracta width. Left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were measured by biplane Simpson''s method. Forty-two children with IDC were studied. The mean follow-up period was 25 months. At initial assessment, 34 children (82%) were taking angiotensin-converting enzyme inhibitors, 25 (60%) furosemide, 27 (65%) β blockers, and 7 (17%) intravenous inotropes. The mean indexed end-systolic volume was 91 ± 51 ml/m2. The mean ejection fraction was 27 ± 16%. MR was mild in 42%, moderate in 19%, severe in 2%, and absent in 35% of patients. MR severity progressed from initial to last evaluation. MR severity was an independent risk factor for lower freedom from death or transplantation. Progression in MR severity increased the annual hazard of death or transplantation by a factor of 2.4 (p = 0.003). In conclusion, MR severity is independently associated with worse clinical status and decreased freedom from death or transplantation in children with IDC. [Copyright &y& Elsevier]

Abstract: Friedreich ataxia (FRDA) is the most common cause of childhood onset ataxia. We report on a 4year old boy who suffered sudden cardiac death and was found to have a dilated cardiomyopathy with left ventricular hypertrophy on post-mortem studies. Molecular genetic testing subsequently confirmed the diagnosis of Friedreich ataxia. To our knowledge, this is the first report of Friedreich ataxia presenting as sudden cardiac death in early childhood. [Copyright &y& Elsevier]