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Regenerative therapies in young hearts with structural or congenital heart disease.

ABSTRACT: Pediatric heart failure (HF) is rare. The prognosis is generally poor. HF is most frequently related to cardiomyopathy or congenital heart disease (CHD). Associated phenotypes are HF with preserved (HFpEF) or reduced ejection fraction (HFrEF); both in children with biventricular or univentricular circulation. Cardiac growth, differentiation, proliferation and consecutively regenerative and repair mechanisms are inversely related to the patient's age; edaphic and circulating cardiac progenitor cells as well; in sum, there are enormous endogenous potentials repairing a diseased heart in particular in young children. Efforts supporting pediatric cardiac regeneration are clearly justified; cell-based therapies have been addressed in small series of children with end-stage HF of either the left or right ventricle, more recently in randomized clinical trials. Different cell populations like autologous bone marrow mononuclear cells, progenitor cells or cardiac derived cells have been injected into coronaries or directly into the myocardium. Beneficial at least transient improvement of cardiac function was observed in patients with dilative cardiomyopathy and CHD, mainly hypoplastic left heart syndrome (HLHS). Cellular repopulation and possibly more crucial, paracrine effects contributed in slowing down progression of pediatric end-stage HF. Our review summarizes the current knowledge in different scenarios of HF by cell-based cardiac therapies in critically ill children. Based on the actual clinical experience future work to distinguish responders from non-responders among other refinements will lead to individualized precision treatment of HF in children, what means a lot to a child on a long list waiting for heart transplantation (HTX).

SUBMITTER: Michel-Behnke I

PROVIDER: S-EPMC6514281 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:One of the most complex forms of congenital heart disease (CHD) involving single ventricle physiology is hypoplastic left heart syndrome (HLHS), characterized by underdevelopment of the left ventricle (LV), mitral and aortic valves, and narrowing of the ascending aorta. The underdeveloped LV is incapable of providing long-term systemic flow, and if left untreated, the condition is fatal. Current treatment for this condition consists of three consecutive staged palliative operations: the first is conducted within the first few weeks of birth, the second between 4 to 6 months, and the third and final surgery within the first 4 years. At the conclusion of the third surgery, systemic perfusion is provided by the right ventricle (RV), and deoxygenated blood flows passively to the pulmonary vasculature. Despite these palliative interventions, the RV, which is ill suited to provide long-term systemic perfusion, is prone to eventual failure. In the absence of satisfying curative treatments, stem cell therapy may represent one innovative approach to the management of RV dysfunction in HLHS patients. Several stem cell populations from different tissues (cardiac and non-cardiac), different age groups (adult- vs. neonate-derived), and different donors (autologous vs. allogeneic), are under active investigation. Preclinical trials in small and large animal models have elucidated several mechanisms by which these stem cells affect the injured myocardium, and are driving the shift from a paradigm based upon cellular engraftment and differentiation to one based primarily on paracrine effects. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of HLHS and other forms of CHD. This article reviews the many stem cell types applied to CHD, their preclinical investigation and the mechanisms by which they might affect RV dysfunction in HLHS patients, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with CHD.

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Regenerative therapies in young hearts with structural or congenital heart disease.

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