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Stem cell therapy has the optimistic goal of regenerating the myocardium as defined by re-growth of lost or destroyed myocardium. As applied to patients with heart failure, many confuse or limit the regenerative definition to just improving myocardial function and/or decreasing myocardial scar formation, which may not be the most important clinical outcome to achieve in this promising field of molecular medicine. Many different stem cell-based therapies have been tested and have demonstrated a safe and feasible profile in adult patients with heart failure, but with varied efficacious end points reported. Although not achieved as of yet, the encompassing goal to regenerate the heart is still believed to be within reach using these cell-based therapies in adult patients with heart failure, as the first-generation therapies are now being tested in different phases of clinical trials. Similar efforts to foster the translation of stem cell therapy to children with heart failure have, however, been limited. In this review, we aim to summarise the findings from pre-clinical models and clinical experiences to date that have focussed on the evaluation of stem cell therapy in children with heart failure. Finally, we present methodological considerations pertinent to the design of a stem cell-based trial for children with heart failure, as they represent a population of patients with very different sets of issues when compared with adult patients. As has been taught by many learned clinicians, children are not small adults!
In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children’s Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children’s Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary “think-tank”. The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute, to describe the “state of the art” of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.
Heart failure is a leading cause of death worldwide. Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration.
A stem cell is defined as a cell with the properties of being clonogenic, self-renewing, and multipotent. In response to intercellular signalling or environmental stimuli, stem cells differentiate into cells derived from any of the three primary germ layers: ectoderm, endoderm, and mesoderm, a powerful advantage for regenerative therapies. Meanwhile, a cardiac progenitor cell is a multipotent cell that can differentiate into cells of any of the cardiac lineages, including endothelial cells and cardiomyocytes.
Stem cells can be classified into three categories: (1) adult stem cells, (2) embryonic stem cells, and (3) induced pluripotential cells. Adult stem cells have been identified in numerous organs and tissues in adults, including bone-marrow, skeletal muscle, adipose tissue, and, as was recently discovered, the heart. Embryonic stem cells are derived from the inner cell mass of the blastocyst stage of the developing embryo. Finally through transcriptional reprogramming, somatic cells, such as fibroblasts, can be converted into induced pluripotential cells that resemble embryonic stem cells.
Four classes of stem cells that may lead to cardiac regeneration are: (1) Embryonic stem cells, (2) Bone Marrow derived stem cells, (3) Skeletal myoblasts, and (4) Cardiac stem cells and cardiac progenitor cells. Embryonic stem cells are problematic because of several reasons: (1) the formation of teratomas, (2) potential immunologic cellular rejection, (3) low efficiency of their differentiation into cardiomyocytes, typically 1% in culture, and (4) ethical and political issues. As of now, bone marrow derived stem cells have not been proven to differentiate reproducibly and reliably into cardiomyocytes. Skeletal myoblasts have created in vivo myotubes but have not electrically integrated with the myocardium. Cardiac stem cells and cardiac progenitor cells represent one of the most promising types of cellular therapy for children with cardiac failure.
The so-called Gerbode ventriculo-atrial defect is a rare defect that permits shunting from the left ventricle to the right atrium. It takes 2 forms, either a deficiency of the atrioventricular membranous septum, or shunting initially through a ventricular septal defect, with atrial shunting occurring through a deficiency in the septal leaflet of the tricuspid valve. In this review, we describe the natural history and outcomes of surgical repair for the variant with shunting through a deficiency at the site of the atrioventricular membranous septum.
From 1990 to 2008, we identified 6 patients from our departmental database who had undergone surgical closure of a congenital defect of the atrioventricular component of the membranous septum. Median age at repair was 1.6 years, with a range, from 0.4 to 19 years. All patients were symptomatic, with 3 having congestive cardiac failure, 2 failing to thrive, and 2 having intolerance to exercise. All had a dilated right atrium demonstrated by echocardiogram, with a mean preoperative gradient measured by echocardiogram to be 109 millimetres of mercury, with a range from 65 to 150 millimetres of mercury.
There was no operative or late mortality. The mean size of the defect was 6.2 ± 2.0 millimetres, with a range from 4 to 8 millimetres. All were closed by insertion of a patch. The mean period of cardiopulmonary bypass was 90.5 ± 11.3 minutes, the mean time of aortic cross-clamping 54.8 ± 6.9 minutes, and the mean length of stay in hospital 4.3 ± 1.0 days. No patient had a residual defect, and only trivial regurgitation of the tricuspid valve was evident by postoperative echocardiography. There were no complications or reoperations.
The membranous ventriculo-atrial defect can be recognized echocardiographically on the basis of dilation of the right atrium in the setting of an unusually high Doppler echocardiogram gradient compared to the ventricular septal defect with shunting only at ventricular level. Since all patients in our series were symptomatic, we recommend surgical closure of all these defects.
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