Regenerative medicine therapy for single ventricle congenital heart disease

Abstract

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- neonate-derived), and different donors (autologous 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.

The effect of stem cells in congenital heart disease

“…Children with many types of single ventricle heart defects normally require three surgeries, including the Norwood, Glenn and Fontan procedure to assist the patient in the growth and survival of life. However, after the last stage, the Fontan procedure, the next step is normally heart transplantation due to volume overload [7]. Volume overload is when there is too much blood in one of the heart chambers for the heart to function correctly.…”

“…However, it has not been achieved yet, it is believed that the goal is to be reached soon by using these therapies with the ongoing clinical trials [13]. Because of the benefits in preclinical studies, there is growing evidence supporting stem cell therapy for children with CHD especially those with single ventricle physiology [7].…”

“…These advances help pave way to treat children with CHD by regenerative medicine [14]. Furthermore, by delivering stem cells into the injured region of the heart, the goal is to regenerate new myocardium, restore groundwork of clinical application [7]. According to Collins and Russell [6], the key elements for stem cell therapy for cardiac repair are the type of cells and the mechanism by which the cell can improve heart function [6].…”

“…By using stem cell therapy, the goal is to promote the engraftment of new, beating cardiomyocytes into where the heart needs it [6]. There are a small but growing number amount of research for stem cell therapy for children with congenital heart disease [7]. Stem cell therapy studies also show the ability for them to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload.…”

“…Congenital heart disease is defined, according to Avolio and colleagues [10], as an "abnormality in heart structure that occurs before birth, while the fetus is developing" [8]. As stated before, congenital heart disease affects 1 in 100 babies every year in the United States [7] and twenty five percent of these infants will require surgery within their first year [11]. The timing of surgeries varies depending on the severity of the defect of each patient, but some patients may need surgical intervention within days or weeks from birth [4].…”