Author + information
- †Department of Pathology, University of Washington, Seattle, Washington
- ‡Department of Bioengineering and Medicine/Cardiology, University of Washington, Seattle, Washington
- §Center for Cardiovascular Biology, University of Washington, Seattle, Washington
- ⋮Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington
- ↵*Reprint requests and correspondence:
Dr. Charles E. Murry, Department of Pathology, University of Washington, 850 Republican Street, Seattle, Washington 98109.
Exciting advances in stem cell biology, combined with continued high morbidity and mortality in heart failure patients, have resulted in a growing number of clinical trials using adult cells to repair injured myocardium (1–6). To date, cell types for clinical trials have been derived from skeletal muscle, bone marrow/peripheral blood, and, most recently, the heart itself. Cell therapy has a demonstrated good safety profile thus far, but results have been variable and benefits modest. In addition to the blood-forming cells, for which it is famous, marrow also has a rich stromal-vascular compartment. Marrow stromal cells are pericyte-like and demonstrate some properties of stem cells, with the ability to give rise to fat, bone, and cartilage (7). Hence, they are often called mesenchymal stem cells (MSCs). There is a large pre-clinical literature on the use of MSCs for cardiac repair showing evidence of improved cardiac function and reduced remodeling in multiple animal models, although their benefits in humans remain uncertain. Originally hypothesized to differentiate into new cardiomyocytes, MSCs are now known to engraft poorly, with the majority persisting less than a week after transplantation. Thus, the explanation for their benefit has shifted from new myogenesis to secretion of paracrine factors. Multiple clinical trials of MSCs for heart repair are under way, and in this issue of the Journal, Bartunek et al. (8) present results from the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) clinical trial.
The purpose of C-CURE was to evaluate the feasibility and safety of delivering lineage-directed bone marrow–derived MSCs for treatment of chronic ischemic heart failure. Patients were on average 58 years of age, had a left ventricular ejection fraction (EF) of 27.6%, and were 1,540 days from the inciting ischemic injury. Iliac crest bone marrow cells were exposed to a cocktail of factors including transforming growth factor-β, bone morphogenetic protein, activin A, fibroblast growth factor 2, cardiotrophin, and α-thrombin. The authors previously reported that these primed bone marrow MSCs demonstrate enhanced cardiac differentiation. To target MSCs to the damaged region, the endocardial surface was electromechanically mapped using a NOGA catheter (Cordis, a Johnson & Johnson company, Bridgewater, New Jersey), and 0.6 to 1.2 billion MSCs were injected in multiple sites within the infarct and border zone using a Myostar catheter (Cordis, a Johnson & Johnson company).
Harvesting marrow locally, shipping it to a central lab for processing, and returning the expanded cells for injection is not a trivial undertaking, and the investigators achieved an ∼70% overall success rate. The 30% of patients for whom cells could not be obtained were dropped from the analysis of the cell-treated cohort, and we are not provided with any demographic details or whether they differed from the patients for whom sufficient cells were generated. No patients experienced adverse clinical events attributable to the cells over the 2-year follow-up, including abnormal tissue growth and increased arrhythmias. Patients who received cells showed evidence of improved function versus the control arm, which received standard of care intervention. Six months after treatment, the cell therapy group had a 7% absolute improvement in EF over baseline, versus a nonsignificant change in the control group. This improvement in EF is dramatic, particularly given the duration between the ischemic injury and cell therapy. It compares favorably with our most potent therapies in heart failure. Interestingly, the higher EF resulted largely from a decrease in end-systolic volume, which differs from pharmacological treatments in which EF improves via reverse remodeling and reduced end-diastolic volume. Cell therapy was also associated with an increase in the 6-min walk test, with a 77-m improvement over the control group but no difference in Vo2max. These findings suggest that treatment with cytokine-primed MSCs is feasible and safe and provides some evidence of enhanced cardiac performance, but only a larger trial will resolve these discrepancies.
The quest to turn adult cells into a renewable source of cardiomyocytes has been under way for >15 years. Previously, Dr. Terzic's group (9–12) reported that cytokine-stimulated human MSCs expressed certain features of cardiomyocytes not found in standard human MSCs, and they termed the population cardiopoietic stem cells. The cardiac properties included expression of cardiac transcription factors (MEF2C, NKX2.5, MESP-1) and, in some instances, expression of contractile proteins without sarcomeric organization. When transplanted into infarcted hearts of immunocompromised rats, cytokine priming improved heart performance compared with naïve human MSCs, and the authors reported MSC-derived human cardiomyocyte formation in the rat heart. Although encouraging, it is important to recognize that the cardiogenic capacity of MSCs has been controversial. Various manipulations have been attempted including treatment with 5-azacytidine, pre-treatment with growth factors, hypoxia pre-conditioning, and genetic engineering (13), and none has robustly yielded definitive cardiomyocytes. The salutary paracrine effects of MSCs have been well documented (14) and could be playing a role for the cardiac primed MSC population as well. The question remains whether there is a significant contribution of force-generating cardiac muscle directly derived from these “cardiopoietic” MSCs? This is difficult to resolve in a clinical trial, but sustained myogenesis by any adult source has been difficult to document, even in animal models.
There has been much variability reported in the results of cardiac cell therapy trials (3), and the National Heart, Lung, and Blood Institute–sponsored Cardiovascular Cell Therapy Research Network has not been able to reproduce the beneficial results reported by others. This may be due, in part, to the small size of the studies but may also be related to study design. In contrast to a classic clinical trial, patients in the C-CURE cell therapy group whose cells did not reach release criteria were excluded from analysis. This may bias the analysis toward a positive effect. For example, we do not know whether this 30% of patients represents a sicker or less-responsive group. Although phase I trials focus on safety, if efficacy endpoints are reported, an intention-to-treat analysis is probably warranted. Despite these limitations, preliminary outcomes reported in the C-CURE trial are encouraging and certainly merit a larger and blinded phase II/III clinical trial with randomization after adequate cells meeting release criteria have been generated.
Pharmacological therapies for heart failure plateaued after the major advances with neurohumoral blockade, and treatment of advanced heart failure has shifted increasingly to mechanical methods. Although these advances have improved outcomes, regenerating the injured myocardium remains the transformative alternative and stem cell treatment remains the most promising approach. The number of clinical trials showing safety and feasibility from adult stem cells is encouraging, but definitive evidence of efficacy remains elusive. Looking ahead, future clinical trials likely will also study pluripotent stem cell derivatives, where new myogenesis is more certain. The C-CURE trial, along with other cardiac cell therapy trials, has provided a strong basis to continue to explore the role of stem cells in the treatment of injured myocardium.
↵* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Murry is a founder of and equity holder in BEAT BioTherapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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