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While in adults major advances in heart failure therapy in patients with dilated cardiomyopathy were documented in the last two decades, research on the mechanism and therapies of heart failure in children with left ventricular dilated cardiomyopathy has lagged behind. Despite the lack of sufficient randomized prospective studies, ACE inhibitors are first line and ß-receptor antagonists are second-line strategies in children. Following the adult guidelines, without having data concerning the pediatric population, mineral corticoids are also accepted in the treatment of pediatric heart failure, while diuretics should only be used to achieve a euvolemic status. In cases of complete left bundle bunch block or prolonged QRS duration, cardiac resynchronization is an option. If these instruments are exploited, and the child is still listed for heart transplantation as destination, evolving therapies like pulmonary artery banding in cases of preserved right ventricular function and cardiac cell therapy in cases of localized ventricular dysfunction might represent additional treatment options. This review summarizes the actual guidelines and provides an outlook for evolving therapies.

Objective: Dilated cardiomyopathy is a leading cause of cardiac death in children. Approximately 30% of children die or need cardiac transplantation in the first year after establishing the diagnosis. New strategies are needed to improve the outcome in this high-risk patient population., Method and Results: We present our experience in 38 patients below the age of three years, who were diagnosed with dilated cardiomyopathy and who were treated at our institution between 2006 and 2012. The treatment strategy involved institution of β-blockers and angiotensin-converting enzyme inhibitors as soon as feasible. In selected cases, pulmonary artery banding or intracoronary autologous bone marrow-derived cell therapy was performed. The median age at presentation was six months (range 1-26 months). The median follow-up age was 16 months (range 2-80 months). Kaplan-Meier analysis of survival after dilated cardiomyopathy diagnosis revealed a one-year survival of 97% and a five-year survival of 86%. The rate of freedom from death or heart transplantation was 82% at one year and 69% at five years. Surviving patients who were free of transplantation, at the follow-up at 25 months (3-80 months), showed a significant improvement in left ventricular ejection fraction (from 19±11 to 46±16%) and left ventricular end-diastolic diameter (z-score from 4.6±2.4 to 1.4±1.6). In addition, the levels of B-type natriuretic peptide improved significantly (from 3330±3840 to 171±825 pg/ml)., Conclusion: Our data suggest that the clinical approach described here may result in a markedly improved medium-term outcome in young children with dilated cardiomyopathy. Further studies are required to evaluate whether these approaches reduce end-points such as transplantation or death.

Very young mammals have an impressive cardiac regeneration capacity. In contrast, cardiac regeneration is very limited in adult humans. The hearts of young children have a higher regenerative capacity compared with adults, as, for example, seen after surgical correction of an anomalous left coronary artery arising from the pulmonary artery or in children with univentricular hearts, who present enormous morphological changes after volume unloading. In addition, the enormous regenerative potential of growing children's hearts is reflected in the spontaneous courses of children with severely deteriorated cardiac function (e.g., patients with dilated cardiomyopathy). The extent of this regenerative capacity and its time dependency remain to be elucidated in the future and should be exploited to improve the treatment of children with severe heart insufficiency.

Introduction: In spite of tremendous progress in the medical and surgical treatment of children with congenital heart disease and dilated cardiomyopathy achieved during the past few decades, for some children a heart transplant remains the only option. Clinically relevant benefits of intracoronary injection of autologous stem cells on cardiac function and remodelling have been demonstrated in adult patients with acute myocardial infarction. Experience with autologous stem cell therapy in children with severe congenital or acquired pump failure is limited to a small number of case reports., Method and Results: Between 2006 and 2010, nine severely ill children were treated with intracoronary infusion of autologous bone marrow-derived mononuclear cells as part of a compassionate therapy in our centre. No procedure-related unexpected adverse events occurred. There was one patient on extracorporeal membrane oxygenation who died of haemorrhage unrelated to the procedure; three patients proceeded to heart transplantation once a donor heart became available. The other five patients showed an improvement with respect to New York Heart Association classification (greater than or equal to 1), brain natriuretic peptide serum levels, and ejection fraction., Conclusion: Similar to adults, intracoronary injection of autologous bone marrow cell is technically feasible and safe for children. On the basis of our data, we propose to perform a pilot study for children with congestive heart failure, to formally assess the efficacy of intracoronary autologous bone marrow cell therapy.

Novel surgical strategies have dramatically improved the initial outcome of newborns with hypoplastic left heart syndrome. However, the single systemic right ventricle remains a major challenge, with limited effectiveness of pharmacologic therapy. The present case documents that the intracoronary administration of autologous bone marrow-derived progenitor cells is technically feasible in a critically ill infant with hypoplastic left heart syndrome and severe heart failure after a hybrid comprehensive stage II procedure. Cell therapy might represent an option before heart transplantation in children with single ventricle physiology presenting with severe heart failure., (Copyright (c) 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

DCM is the most common cardiomyopathy in childhood. Effectiveness of anticongestive therapy is limited in most cases and about one-third of children diagnosed with DCM die or receive heart transplantation within the first year after diagnosis. Cardiac stem cell transplantation has become a promising therapy to treat heart failure in adult patients. Based on these promising results, the cardiac stem cell therapy might also represent a new therapeutic option particularly in young children. The present case documents for the first time intracoronary administration of autologous bone marrow-derived progenitor cells in a critically ill two-yr-old child with severe heart failure caused by DCM. Because of progressive worsening of the clinical condition despite maximal anticongestive treatment, the decision to perform autologous stem cell therapy was made. Cardiac stem cell therapy proved to be technically feasible, was associated with improvement in cardiac function, and might represent an option before heart transplantation in children with severe heart failure. [ABSTRACT FROM AUTHOR]

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3 -deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3 -deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5 , restores normal concentrations of soluble cardiac proteins in juvenile Bag3 -deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3 -deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment. [Display omitted] • Inactivation of Bag3 in CMs initiates hypertrophic cardiomyopathy in juvenile mice • Juvenile but not late stage Bag3 -deficient CMs show increased autophagic flux • Inactivation of Atg5 does not improve cardiac function in juvenile Bag3 -cKO mice • Treatment with chloroquine normalizes cardiac function in juvenile Bag3 -cKO mice • Human BAG3P209L heart samples show similar changes as in Bag3 -cKO mice [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures.Methods: We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.Results: The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes.Conclusions: Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants. [ABSTRACT FROM AUTHOR]