Pediatric Dilated Cardiomyopathy Research Articles

Uric acid elevation in pediatric patients with dilated cardiomyopathy and prediction of mortality

Background and aimsPediatric dilated cardiomyopathy (DCM) is a primary cause of heart failure, highlighting the urgent need for effective prognostic markers.MethodsWe performed a single-center retrospective study involving 145 children diagnosed with DCM, with a median follow-up period of 4.0 months (interquartile range: 6.2–108.4 months). The relationship between serum uric acid (SUA) levels and all-cause mortality was assessed using Kaplan–Meier survival curves, multivariate Cox proportional hazard models, and restricted cubic spline (RCS) models.ResultsOf the 145 children with DCM (median age 5.7 years; 61.4% male), 45 (31%) died within 1 year, and 65 (44.8%) died during the maximum follow-up period. In adjusted multivariate Cox regression models, each log2 SUA increase was linked to a higher risk of 1-year mortality [hazard ratio (HR), 2.66; 95% confidence interval (CI), 1.41–5.01] and overall mortality (HR, 1.97; 95% CI, 1.15–3.37). The highest SUA tertile showed a greater risk of mortality at 1 year (HR, 4.26; 95% CI: 1.5–12.06) and during the maximum follow-up (HR, 2.56; 95% CI: 1.06–6.16) compared with the lowest tertile. RCS models indicated an inverted L-shaped association between baseline SUA levels and overall mortality risk, with age-stratified analyses revealing a linear and U-shaped relationship in children ≤10 and >10 years, respectively. Further age-stratified analyses highlighted the modifying effect of age on this association.ConclusionElevated SUA levels are a significant predictor of mortality in pediatric DCM, with a pronounced impact on children under 10 years of age. Therefore, SUA levels could serve as potential biomarkers for risk stratification in this population.

Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis.

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM.

Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

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. 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). 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. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

Iron deficiency and anemia in pediatric dilated cardiomyopathy are associated with clinical, biochemical, and hematological markers of severe disease and adverse outcomes

BackgroundThere is limited evidence regarding the prevalence and impact of iron deficiency (ID) in children with dilated cardiomyopathy (DCM). MethodsRetrospective single-centre review of all children between 2010-2020 with a diagnosis of DCM and complete iron studies. ID was defined as ≥ 2 of ferritin < 20 μg/L, iron < 9 μmol/L, transferrin > 3 g/L or transferrin saturation < 15%. Clinical and laboratory indices, and freedom from a composite adverse event (CAE) of mechanical circulatory support, heart transplant or death were compared between children with and without ID. ResultsOf 138 patients with DCM, 47 had available iron studies. Twenty-nine (62%) were iron deficient. Children with ID were more likely to be receiving inotropes (17, 59%, P =.005) or invasive/non-invasive ventilation (13, 45%, P =.016) than those who were iron replete. They had a higher incidence of anemia (22, 76%, P =.004) and higher NT-proBNP (1590pmol/L, IQR 456–3447, P =.001). Children with ID had significantly less freedom from the CAE at 1-year (54±10%), 2-years (45±10) and 5-years (37±11%) than those without (P =.011). Iron deficiency and anemia were the only significant predictors of the CAE on univariate Cox regression. ConclusionsIron deficiency is highly prevalent in children with DCM. Iron studies are under-measured in clinical practice, but ID is associated with severe heart failure, and an increased risk of the CAE. The need for iron replacement therapy should be considered in children who present in heart failure with DCM.

Abstract 18567: Acute Inhibition of Phosphodiesterase 1 (PDE1) Decreases Tension Generation in Pediatric Heart Failure

Introduction: Children with heart failure (HF) due to dilated cardiomyopathy (DCM) or single ventricle congenital heart disease (SV) ultimately require heart transplantation due to the lack of effective medical therapies. Inhibition of PDE1 (PDE1i) is currently being investigated in adult HF, however it is unclear if PDE1i use should be extrapolated to pediatric HF. Objective: To evaluate the acute effect of PDE1i on loaded myocardial contractility in pediatric DCM and SV trabeculae. Methods: Hearts were obtained from DCM (N=25) and SV (N=27) children who underwent transplant between 2010-2020. Right ventricular trabeculae are freshly isolated and mounted in a multi-chamber muscle bath. Ex vivo contractile response of isolated trabeculae was measured in response to 10uM PDE1i, the non-selective β-agonist isoproterenol (Iso), and untreated. To assess contractile response with increased cyclic adenosine monophosphate (cAMP) from β-adrenergic stimulation, a subset of baths received Iso and PDE1i. Percent change in max tension was determined by the difference between max tension and baseline tension, divided by baseline tension. Results: In pediatric DCM and SV trabeculae, acute PDE1i resulted in lower max tension generation when compared to untreated trabeculae (DCM p=0.003 and SV p=0.01). In DCM trabeculae, % change in tension was also lower with PDE1i when compared to Iso (p=0.0053) however there was only a trend toward significance in SV (p=0.06). There was no difference between % change in tension between Iso and PDE1i+Iso in either DCM or SV. Conclusions: Although PDE1 has high expression and activity in human cardiomyocytes, acute PDE1i treatment of explanted trabeculae results in decreased max tension generation. Even in the setting of elevated cAMP, PDE1i does not alter max tension generation. Thus, while there may be beneficial effects of PDE1i in pediatric HF, the consequences are unlikely related to a direct increase in cardiomyocyte contractility.

Abstract 18860: Molecular Pathways Altered in Pediatric Dilated Cardiomyopathy Hearts Are Dependent on Disease Etiology

Introduction: Dilated cardiomyopathy presents a significant clinical burden in pediatric patients due to limited effective treatment options. This study hypothesizes molecular alterations in the heart of pediatric dilated cardiomyopathy (DCM) patients are dependent on specific etiologies. By understanding the molecular mechanisms underlying different etiologies, we aim to enhance diagnostics and guide future targeted therapies. An advanced understanding of the molecular mechanisms of DCM holds potential to transform pediatric cardiovascular care. Methods: RNA was extracted from the IRB approved University of Colorado's pediatric cardiac tissue bank. Samples included non-failing (NF), idiopathic dilated cardiomyopathy (IDCM), myocarditis, and left-ventricle non-compaction (LVNC) hearts. RNA-seq was performed using the Illumina HiSeq 4000 platform, and aligned using the TOPmed RNA-seq pipeline. Statistical analysis between NF and each etiology was performed to identify fold changes and q-values. Gene expression analysis was further examined using Ingenuity Pathway Analysis (Qiagen). Results: Demographics of patient samples were as follows: NF (N=23, % male=61%, Median age=13.65 years, Interquartile range (IQR)=8.6), IDCM (N=20, % male=55%, Median age=9.83 years, IQR=8.98), myocarditis (N=4, % male=75%, Median age=0.35 years, IQR=0.1), LVNC (N=3, % male=33.3%, Median age=0.27 years, IQR= Undetermined). Comparisons between NF versus IDCM, NF versus myocarditis, and NF versus LVNC hearts revealed noteworthy differences in gene expression patterns. Pathways associated with IDCM related to inflammation and immune response trends, whereas DNA repair and cellular damage were strongly associated with myocarditis. Lastly, analysis of LVNC hearts suggest pathways associated with ischemic remodeling. Conclusions: In conclusion, our study provides insights into gene expression patterns associated with different etiologies of DCM in pediatric patients. Distinct patterns were observed between non-failing and IDCM, myocarditis, or LVNC hearts. These findings have implications for improving diagnostics and guiding targeted therapies in pediatric DCM management.

Circulating and Cardiac Tissue miRNAs in Children with Dilated Cardiomyopathy.

microRNAs (miRs) are small non-coding single-stranded RNAs that regulate gene expression. We previously evaluated expression of miRs in the cardiac tissue of children with dilated cardiomyopathy (DCM) using miRNA-seq. However, a comparative analysis of serum and cardiac miRs has not been performed in this population. The current study aimed to evaluate miR levels in the serum of pediatric DCM patients compared to healthy non-failing (NF) donor controls and investigate the association between miR levels in tissue and sera from the same pediatric DCM patients. Defining the relationship between serum and tissue miRs may allow the use of circulating miRs as surrogate markers of cardiac miRs. miR levels were investigated through miR-array in sera [n = 10 NF, n = 12 DCM] and miR-seq in tissue (n = 10 NF, n = 12 DCM). Pathway analysis was investigated using the miR enrichment analysis and annotation tool (miEAA) for the five miRs commonly dysregulated in the sera and tissue of pediatric DCM patients. Functional analysis of miRs commonly dysregulated in the sera and tissue of pediatric DCM patients suggests altered pathways related to cell growth, differentiation and proliferation, inflammation, mitochondrial function, and metabolism. These findings suggest that circulating miRs could reflect altered levels of cardiac tissue miRs.

The microtubule signature in cardiac disease: etiology, disease stage, and age dependency

Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common experimental models has been incompletely defined. Here, we assessed the tubulin signature in a large set of human cardiac samples and myocardium of animal models with cardiac remodeling caused by pressure overload, myocardial infarction or a gene defect. We studied levels of total, acetylated, and detyrosinated α-tubulin and desmin in cardiac tissue from hypertrophic (HCM) and dilated cardiomyopathy (DCM) patients with an idiopathic (n = 7), ischemic (n = 7) or genetic origin (n = 59), and in a pressure-overload concentric hypertrophic pig model (n = 32), pigs with a myocardial infarction (n = 28), mature pigs (n = 6), and mice (n = 15) carrying the HCM-associated MYBPC32373insG mutation. In the human samples, detyrosinated α-tubulin was increased 4-fold in end-stage HCM and 14-fold in pediatric DCM patients. Acetylated α-tubulin was increased twofold in ischemic patients. Across different animal models, the tubulin signature remained mostly unaltered. Only mature pigs were characterized by a 0.5-fold decrease in levels of total, acetylated, and detyrosinated α-tubulin. Moreover, we showed increased desmin levels in biopsies from NYHA class II HCM patients (2.5-fold) and the pressure-overload pig model (0.2–0.3-fold). Together, our data suggest that desmin levels increase early on in concentric hypertrophy and that animal models only partially recapitulate the proliferated and modified tubulin signature observed clinically. Our data warrant careful consideration when studying maladaptive responses to changes in the tubulin content in animal models.Graphical

Pulmonary Artery Banding -Original, Current, and New Indications for Pulmonary Artery Banding-

First performed in the early 1950s in children with a large left-to-right shunt or single ventricle and excessive pulmonary blood flow, pulmonary artery banding (PAB) is a palliative surgery designed to relieve symptoms. After advances in cardiopulmonary bypass techniques in the 1980s allowed surgeons to perform corrective surgery even in infants, PAB has continued to play a palliative role in balancing the pulmonary to systemic blood flow ratio in critical situations. PAB is also used to retrain the left ventricle in patients with transposition of the great arteries to prepare them for the arterial switch procedure, either following late presentation or following prior atrial repair. Another role played by PAB is to train the left ventricle in patients with congenitally corrected transposition of the great arteries, not only for the purpose of retraining the sub-pulmonary left ventricle but also as an early prophylactic approach in newborns to avoid the severe tricuspid regurgitation sometimes associated with a morphologic right ventricle in the systemic position. Currently, PAB has two indications: 1. to reduce the pulmonary blood flow and relieve the symptoms of congestive heart failure, and 2. to train the sub-pulmonary ventricle for future corrective surgery. Recently, PAB has been successfully employed to treat children with dilated cardiomyopathy (DCM), a disease that has shown considerably increased morbidity and mortality rates and indications for heart transplantation; some of the patients thus treated have shown improved left ventricular function, allowing them to be taken off the waiting list for heart transplantation. In this paper, we review the original and current indications for PAB and explain the surgical technique and strategy. We also present a literature review of the new indications for PAB in patients with pediatric DCM, and compare outcomes in Japan with those in other countries.

Generation of a human induced pluripotent stem cell line from a pediatric heart failure patient with de novo DNM1L mutation

We generated a new iPSC line (LCHi003-A) from the pediatric dilated cardiomyopathy patient carrying the de novo mutation on DNM1L gene. The new iPSC line expressed high pluripotent markers and were capable to differentiate into trilineage.

Recent studies on dilated cardiomyopathy caused by TTN mutations in children

The mutations of TTN gene that encodes titin are the most common mutation type among the genetic causes of dilated cardiomyopathy (DCM). This article reviews the worldwide studies on potential molecular pathogenesis (transcription, post-translational modification, etc.), clinical phenotypes, and gene therapies of pediatric DCM caused by TTN mutations, with the hope of providing a reference for the precision treatment of pediatric DCM caused by TTN mutations.

Clinical profile and outcomes of childhood dilated cardiomyopathy - A single-center three-decade experience.

Dilated cardiomyopathy (DCM) is an important cause of heart failure (HF) among children. Research on pediatric DCM remains surprisingly scarce. The primary objective of the study was to evaluate the clinical profile and outcomes of pediatric DCM and the secondary objective was to study the predictors of outcome. We enrolled all patients with cardiomyopathy who presented to us between 1990 and 2020 and were younger than 18 years. During the 30-year study period, we identified 233 cases of pediatric cardiomyopathy. One hundred and nineteen (51%) cases had DCM. This retrospective cohort was analyzed to study their outcome and the possible predictors of outcome. Nearly, 8% presented in the neonatal period, and 37% in infancy. The most common mode of presentation was dyspnea on exertion (71%). Ninety-three patients presented in heart failure (78%). The median left ventricular dimension z-score in diastole was 4.3 (range 2.5-9.06). The median left ventricle (LV) ejection fraction was 31%. Seventy-two percent of this cohort were on angiotensin-converting-enzyme inhibitors, 40% on aldosterone antagonists, and 47% on beta-blockers. One-third had syndromic, metabolic, genetic, or any secondary cause identified. Twenty-seven patients satisfied the three-tiered clinical classification for the diagnosis of probable acute myocarditis. Over a mean follow-up of 3.29 years, 27% were lost to follow-up. Among the remaining patients who were on follow-up (n = 86), 39 (45%) died, 31 (36%) recovered, and 16 (18%) had persistent LV dysfunction. Heart Failure was the most common cause of death. Eight patients in this cohort (4.2%) had thromboembolic phenomena. Nine had sustained ventricular arrhythmias and six had atrial/junctional arrhythmias. Among the various risk factors studied, only infantile onset had a significant relationship with death or ventricular arrhythmias (P value- 0.05). The 5-year survival rate of DCM patients was 59%. A reasonably good percentage of our population showed recovery of the left ventricular function (36%). Only infantile onset had a significant relationship with death or ventricular arrhythmias. The outcome in our DCM cohort is similar to other population cohorts.

Heart rate reduction as a marker to optimize carvedilol treatment and enhance myocardial recovery in pediatric dilated cardiomyopathy.

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children. Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol. Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged <18years) between 2013 and 2020, with LVEF <40% and treated with carvedilol. Carvedilol was up titrated to the maximal tolerated dose or to 1mg/kg/day. Echocardiographic data on left ventricular function and dimension were collected. The relationship between HRR and LVEF, left ventricular end-diastolic (LVEDd) and end-systolic diameter (LVESd) was assessed before and after HRR with carvedilol, using regression analysis. Results: 100 patients were enrolled (M: 51%; age 7 ± 8years). The mean LVEF was 30.2 ± 10% before treatment and 43.7 ± 9.6% after treatment, at the maximum therapeutic dose (p < 0.0001). There was a positive relationship between HRR and increase in LVEF (R 2 = 0.06, p = 0.014). A HRR of >20% correlated with an improvement in LVEF >13%. At 3years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% (p < 0.0001). No deaths or heart transplant occurred during follow-up. Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children.

Serum from pediatric dilated cardiomyopathy patients promotes dysregulation of cardiolipin biosynthesis and mitochondrial dysfunction in primary cardiomyocytes

Pediatric dilated cardiomyopathy (DCM) is a devastating and poorly understood disease with most clinical treatment paradigms extrapolated from the adult population. Our studies showed that aspects of metabolism and mitochondrial function are dysregulated in pediatric hearts. Cardiolipin (CL), a unique phospholipid in the inner mitochondrial membrane, is essential for optimal mitochondrial function and was shown to be dysregulated in failing adult and pediatric human heart.

Abstract 14006: Circulating microRNAs Predict Recovery in Pediatric Dilated Cardiomyopathy Patients

Introduction: microRNAs (miRs) are small single stranded RNAs capable of targeting expression of several genes. Circulating miRs are stable and can be important biomarkers of disease progression and diagnosis. Hypothesis: We hypothesized circulating miRs could be a reliable prognostic biomarker of recovery for pediatric dilated cardiomyopathy (DCM). Methods: TaqMan Open Array miR panel (ThermoFisher Scientific) was used to investigate expression of 381 circulating miRs. Samples originated from the Pediatric Cardiomyopathy Registry (PCMR) and were collected within 3 months of a new diagnosis of DCM. Inclusion criteria included &lt;18 years of age at diagnosis of idiopathic or familial DCM (EF&lt;50% or left ventricular end-diastolic dimension [LVEDd] z-score ≥+2). Patients with DCM secondary to musculoskeletal diseases or anthracycline toxicity were excluded. Primary outcomes, occurring within 1 year of enrollment, were defined as: [1] Death, transplant (tx) listing or initiation of mechanical circulatory support; [2] Recovered- normalization of ventricular size and function (EF≥50% and LVEDd z-score &lt;+2) or [3] Stable- persistent DCM with EF&lt;50% or LVEDd z-score ≥+2. Statistical analysis included random forest, hierarchical clustering and area under the receiver operator curve (AUC). Results: N=10 subjects were included in Group 1, of which 70% were female, 6 were white, 2 Hispanic and 3 of other/unknown races, median age 9.5y. N=5 samples were included in Group 2, of which 60% were female, 3 were white, 1 black and 1 native American, median age 1.9y. N=20 samples were included in Group 3, of which 40% were female, 10 were white, 5 black, 1 Pacific islander, 2 Hispanic and 4 of other/unknown races, median age 2.1y. The top 3 miRs differentiating Group 2 (Recovered) from Group 1 (Death/Tx) (AUC of 0.92) were hsa-miR-655, -410 and -636. The top 3 miRs differentiating Group 2 (Recovered) from Group 3 (Stable) were hsa-miR-17, -410 and -345 (AUC of 0.76). Conclusions: These results indicate circulating miRs can predict recovery in the pediatric DCM population. A unique biomarker signature of miRs specific to patients who have the potential to recover would improve risk stratification of this population.

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Effect of β-Blocker Therapy on the Level of Soluble ST2 Protein in Pediatric Dilated Cardiomyopathy.

Background and Objectives: A prognosis for kids with pediatric dilated cardiomyopathy (PDCM) is urgently needed to identify high-risk patients. This study aimed to determine the association of levels and soluble suppression of tumorigenicity 2 (sST2) and medical therapy of β-blocker inhibitors with the risk of adverse events in PDCM. Materials and Methods: A total of 124 patients with PDCM were enrolled after admission from 2 centers in China and followed up for adverse events (death, cardiac transplantation, and heart-failure-related rehospitalization). Based on a median sST2 level and the usage of β-blocker inhibitors, patients were divided into four groups. The Cox proportional hazard model was used to assess the risk of incident adverse events. Results: The median level of sST2 was 23.77 ng/mL, and 53 (42.7%) patients received β-blocker treatment. Over a median follow-up of 678 days, 37 (29.8%) adverse events occurred. Compared with patients with sST2 < median and without β-blocker, patients with sST2 ≥ median and without β-blocker (HR: 7.01; 95% CI: 1.21–40.45), followed by those with sST2 ≥ median and use of β-blocker had the highest risk of adverse events (hazard ratio (HR): 5.51; 95% confidence interval (CI): 1.17–25.84). However, a significant association was not observed in patients with sST2 < median and use of β-blocker. These associations were consistent across different subgroups. Conclusions: A higher level of sST2 was associated with a higher risk of adverse events in patients with PDCM, and β-blocker treatment for children with high levels of sST2 can effectively avoid adverse events.

Serum from pediatric dilated cardiomyopathy patients promotes dysregulation of cardiolipin biosynthesis and mitochondrial dysfunction in primary cardiomyocytes

Pediatric dilated cardiomyopathy (DCM) is a devastating and poorly understood disease with most clinical treatment paradigms extrapolated from the adult population. Our studies showed that aspects of metabolism and mitochondrial function are dysregulated in pediatric hearts. Cardiolipin (CL), a unique phospholipid in the inner mitochondrial membrane, is essential for optimal mitochondrial function and was shown to be dysregulated in failing adult and pediatric human heart. Our objective is to investigate if serum circulating factors from pediatric DCM patients can remodel CL resulting in mitochondrial dysfunction in vitro, similar to what is observed in the failing pediatric heart. Using a novel in vitro model that consists of treating neonatal rat ventricular myocytes (NRVMs) with serum from pediatric DCM patients or from non-failing (NF) healthy controls, mitochondrial respiration was assessed using the Agilent Seahorse, and reactive oxygen species (ROS) was assessed using Electron Paramagnetic Resonance Spectroscopy. Relative mtDNA copy number was determined by qPCR and expression of enzymes involved in CL biosynthesis were analyzed using RT-qPCR. Mass-spectrometry was used to quantitate total and specific CL species and to investigate the metabolite composition of NRVMs treated with NF or DCM serum. While mitochondrial ROS and mtDNA copy number were not significantly altered, we show that DCM serum decreases mitochondrial function, which is associated with alterations in CL content and composition and the downregulation of enzymes implicated in CL biosynthesis. Analysis of metabolite content showed an alteration of pathways involved in fatty acid metabolism, mitochondrial biogenesis and regulation of β-oxidation by PPARα. In conclusion, pediatric DCM serum circulating factors can promote CL remodeling resulting in mitochondrial dysfunction in primary cardiomyocytes. These findings suggest that CL could be a novel therapeutic target for this particular population.

Outcomes of Dilated Cardiomyopathy in Japanese Children - A Retrospective Cohort Study.

There has been no nationwide survey on the prognosis of pediatric dilated cardiomyopathy (DCM) in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate in pediatric patients with DCM in Japan.Methods and Results:In this multicenter retrospective observational study, data were reviewed for 106 patients aged <18 years who had been diagnosed with DCM at any 1 of 18 Japanese institutions between 1990 and 2014. The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years. Most DCM patients were diagnosed because of symptoms of heart failure. On echocardiography, the median left ventricular end-diastolic dimension z score was 5.4 and fractional shortening was 0.10. Freedom from death or transplantation rates at 1, 3, 5, 10, and 20 years after diagnosis were 76%, 66%, 64%, 58%, and 43%, respectively. Freedom from death rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively. The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively, suggesting that only 15% of patients in Japan underwent heart transplantation within 5 years of diagnosis. In Japan, the prognosis of pediatric DCM is poor and the rate of heart transplantation is low.

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy.

BackgroundPediatric dilated cardiomyopathy (DCM) is a well‐known clinical entity; however, phenotype–genotype correlations are inadequately described. Our objective was to provide genotype associations with life‐threatening cardiac outcomes in pediatric DCM probands.Methods and ResultsWe performed a retrospective review of children with DCM at a large pediatric referral center (2007–2016), excluding syndromic, chemotherapy‐induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life‐threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, P=0.21). TTN truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, P=0.01), but life‐threatening cardiac outcomes occurred in both infants and teenagers with these TTN variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with MYH7 variants between amino acids 1 and 600.ConclusionsSarcomeric variants were common in pediatric DCM. We demonstrated genotype‐specific associations with age of diagnosis and cardiac outcomes. In particular, MYH7 had domain‐specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.