Stem cells on a new stage: Treatment of hypoplastic left heart syndrome

For the last decade, adult patients with ischemic heart disease have been the subject of a series of early-phase trials to investigate the therapeutic use of stem cells for myocardial recovery. Numerous cell types and formulations, dosages, timing courses, and modes of delivery have been investigated, with the unifying premise that a cell-based therapy could promote functional recovery or regeneration of infarcted myocardium. Although safety end points have been consistently achieved, however, the efficacy of stem cell therapy to enhance ventricular function has been mixed in these early trials. With the Transcoronary Infusion of Cardiac Progenitor Cells in Hypoplastic Left Heart Syndrome (TICAP) trial, however, stem cell therapy was evaluated for the first time in a population of infant patients with congenital heart disease. Although this was a small, phase I trial (7 treated and 7 control patients), the initial results at 18 months of follow-up not only showed safety and feasibility but also showed striking improvements in systemic ventricular function, somatic growth, and quality of life.1 The 3-year follow-up of these patients, published by Tarui and colleagues2 in this month’s issue of the Journal, shows a persistence of these beneficial effects and provides new evidence to address questions that have been asked by stem cell biologists and clinicians alike since the initial translation of stem cells for the treatment of cardiovascular disease. Among patients with congenital heart disease, those born with hypoplastic left heart syndrome continue to have relatively bleak outcomes. As the Surgical Ventricular Reconstruction trial showed us, even in the best hands and in the setting of a well-conducted clinical trial, transplant-free survival at 1 year was only 64% to 74%, and transplant-free survival at 5 years was as low as 60% to 64%.3,4 Although the reasons for this attrition are clearly multifactorial, systemic ventricular dysfunction has been shown to be an independent predictor of mortality.5 A therapy able to boost systemic ventricular performance therefore has the potential to mitigate significantly the morbidity and mortality seen in these patients. Stem cells have previously been applied to children with end-stage cardiomyopathy and hypoplastic left heart syndrome in isolated cases and small series.6 These reports showed dramatic improvement in ventricular function, reduction in brain natriuretic peptide, and improvement in heart failure symptoms. It was the TICAP trial, however, led by Hidemasa Oh and colleagues, that was the first to evaluate formally a cell-based therapy for children with congenital heart disease in the setting of a clinical trial. From among the stem cell types available, the TICAP trial used cardiosphere-derived cells (CDCs), which are a heterogeneous population of CD105+ and CD45− mononuclear cells that can be isolated and expanded ex vivo from cardiac tissue biopsy samples. The safety and functionality of CDCs have been backed by a decade of preclinical studies, as well as a recently completed phase 1b clinical trial.7 In the TICAP trial, autologous CDCs were delivered intracoronarily approximately 4 to 5 weeks after the stage 2 or stage 3 operations.1 The initial results at 18 months after injection of the CDCs reported no adverse events related to the therapy and a mean improvement in ejection fraction from 46.9% ± 4.6% to 54.0% ± 2.8% (vs a change of 46.7% ± 4.4% to 48.7% ± 6.7% in the control group). Other benefits included significant reductions in the diameter of the tricuspid valve annulus and the indexed end-systolic and end-diastolic volumes of the right ventricle. In addition, a significant improvement was observed in the z scores for height and weight at 18 months relative to baseline in the cell-treated patients, whereas there was no change in growth in the control group. Finally, significant reductions in heart failure status, brain natriuretic peptide levels, and number of coil interventions were also found in the treatment group. Whether stem cell–related benefits to myocardial function can and do persist beyond the initial follow-up period has remained an unanswered question since the completion of many stem cell trials in adults. Given the paucity of stem cells retained in the myocardium, even 24 hours after transplant, there is legitimate concern regarding sustained benefits to ventricular function. The discrepancy between poor cell retention and observed improvements in ventricular performance, at least in short-term follow up, has been addressed in recent preclinical studies that have consistently pointed to paracrine-mediated effects as the driver of myocardial recovery, rather than the differentiation and retention of the cells themselves.8 Still, whether these effects trigger long-lasting changes or only temporary effects has remained largely unknown. The 3-year follow-up data from the TICAP trial therefore offers one of the first opportunities to examine the durability of the outcomes found in stem cell–treated patients. Tarui and colleagues found that changes in right ventricular size and function, tricuspid annular diameter, number of unplanned catheter-based interventions, and quality of life remained superior in the stem cell–treated patients relative to the control group. Interestingly, bivariate analysis revealed the best responses to CDC infusion among this 7 patient cohort occurred in those with the smallest size, youngest age, or lowest ejection fraction. In terms of these being independent predictors of “responsiveness” to cell therapy, multivariable analysis of results from future trials with a larger sample size will be needed to verify these preliminary findings. These limitations aside, the concept that younger, sicker patients may have a more robust response to stem cell infusion is intriguing and supported by a number of emerging lines of evidence. First, our laboratory has shown that CDCs derived from neonates significantly outperform those derived from adults in both in vivo and in vitro assays of stem cell function, including a rodent model of myocardial infarction—a model to test regeneration.9 In addition, our laboratory has shown that the number of cardiac progenitor cells within the myocardium decreases in an age-dependent fashion, with the greatest number of stem cells identified in neonatal and infant myocardium relative to older children, teenagers, and adults. We have also shown that in the setting of heart failure, however, children have a relatively increased number of cardiac stem cells, and the number of these cells is no longer age dependent. Together these findings suggest that children, especially those with ventricular dysfunction, have a larger and more robust compartment of cardiac stem cells. The role of endogenous cardiac stem cells in myocardial repair and their response to stimuli such as exogenous stem cell infusion is still unclear but may account in part for the significant and sustained response observed in children in the TICAP trial. In a swine model, for instance, it was shown that injection of bone marrow–derived mesenchymal stem cells after myocardial infarction led to a 6-fold increase in the recruitment of endogenous c-kit+ cardiac stem cells to the peri-infarct zone, suggesting that exogenous cell therapy may play a role in stimulating resident cardiac stem cells to participate in myocardial repair.10 In neonates and infants, these responses may in fact be amplified and result in more pronounced therapeutic effects. A number of other stem cell trials for children with hypoplastic left heart syndrome are currently planned or ongoing.11 It is hoped that lessons learned from the TICAP trial and these others will provide insight into the optimal cell type, delivery strategy, and timing of such therapy. For instance, whereas the TICAP trial used intracoronary delivery of CDCs 4 to 5 weeks postoperatively, the ongoing trial at the Mayo Clinic and our own planned trial at the University of Maryland will use direct intramyocardial injection at the time of the stage II operation of cord blood stem cells and mesenchymal stem cells, respectively. Given the variation in stem cell type and study design among these trials, continued preclinical evaluation is urgently needed to inform future protocols optimally. Large animal models relevant to congenital heart disease as well as mechanistic studies aimed at delineating the specific responses to stem cell therapy in the extracellular matrix, by cardiomyocytes, and under epigenetic control are of critical importance. Meanwhile, the TICAP trial and its 3-year follow-up should garner enthusiasm for stem cell therapy and establish the basis for nonischemic ventricular dysfunction in pediatric patients as an emerging indication for stem cell therapy.