Discussion
The C-CURE clinical trial assessed cardiopoietic stem cell intervention as an adjunct to chronic heart failure management. This is the first application of guided stem cells for targeted regeneration of a failing organ. Lineage priming of bone marrow stem cells from patients with ischemic heart failure was shown to be feasible. Administration of derived autologous cardiopoietic stem cells into the hibernating myocardium of patients with heart failure was safe. The study demonstrated consistent improvement of the LVEF with cardiopoietic stem cell therapy compared with standard of care. By introducing lineage guidance into the cell therapy protocol, the C-CURE trial provides initial clinical evidence of a new approach to cardiovascular regenerative medicine.
To date, clinical studies have used bone marrow stem cells in their native lineage–unspecified state, as unfractionated or purified cell products largely in the setting of acute or subacute myocardial infarction. The molecular substrate of advanced heart failure requires distinct regenerative strategies adequate to restore parenchymal integrity and prevent progressive remodeling. Human bone marrow stem cells are a desirable source for organ repair due to accessibility for harvest, propensity to propagate in culture, favorable biological profile, and extensive clinical experience. However, when derived from heart failure patients, bone marrow mesenchymal stem cells demonstrate latent plasticity with variable spontaneous capacity to instigate regeneration, Recent studies have used excised heart tissue, obtained at the time of cardiac bypass or by endomyocardial biopsy, to anatomically match the stem cell source to the target organ of repair. The rationale for the present clinical study is based on pre-clinical evidence that pre-emptive guidance optimizes repair potency despite a noncardiac source of stem cell derivation.
Induction of the cardiopoietic stem cell state is intended to ensure the regenerative benefit of mesenchymal stem cells derived from patients with heart failure. Cardiopoiesis is promoted through replication of natural cues decoded from endoderm-mediated cardiogenic guidance of the mesoderm. A set of recombinant factors here converted mesenchymal stem cells from patients with ischemic heart failure to yield a Good Manufacturing Practice grade, scalable biologics meeting pre-set quality control release criteria. Repeat manufacturing runs were imposed when the stem cell proliferative capacity was insufficient to derive the target dose. The inability to grow a critical mass of cells in and of itself has been suggested to be an outcome prognosticator. However, post-hoc analysis of data from patients not meeting cell quality inclusion criteria did not support this premise. Rather, in this study, bone marrow harvest, specimen anticoagulation, and/or cryopreservation were noted on retrospective quality review to compromise starting material and ultimate cell yield in line with previous studies. In this way, the quality standards pre-imposed in this study ensured that cells released for delivery into patients were adherent to a phenotype associated with repair benefit.
From time of delivery and through follow-up, cardiopoietic stem cell transplantation demonstrated a safety profile equivalent to standard of care. Endomyocardial delivery was associated acutely with a transient increase in cardiac enzymes, remaining within values previously reported with myocardial injections. Corroborating pre-clinical findings, no long-term evidence of uncontrolled tissue growth or proarrhythmogenic risk was associated with exposure to cardiopoietic stem cells. Prospective, 2-year surveillance confirmed clinical safety.
Although not powered as a therapeutic efficacy trial, a benefit for left ventricular function was documented here with cardiopoietic stem cell treatment. Although in principle, varying cell doses and injection numbers could confound interpretation, pre-clinical data showed no dose dependence on outcome within the range used here. Improved LVEF, as observed at 6 months in the present study, is a powerful predictor of beneficial cardiovascular outcome in heart failure, and was here associated with a reduced ESV, consistent with reversal of pathological remodeling.
Study Limitations
The present study was limited in assessing the change in myocardial regeneration or perfusion because modalities, such as magnetic resonance imaging and single-photon emission computed tomography, were precluded due to incompatibility with patient population or unavailability at all participating sites. A composite score comprising, in addition to changes in cardiac structure and function, quality of life and clinical endpoints improved with cardiopoietic stem cell therapy beyond standard of care alone. These data collectively highlight the potential of lineage-specified stem cells to meet the regenerative requirements of ischemic heart failure, particularly in select patients in whom revascularization, resynchronization, and pharmacotherapy failed to restore pump function. In this initial clinical experience, procurement and delivery of cardiopoietic stem cells, as well as safety and efficacy profiles, showed equivalence across distinct socioeconomic and health care settings, an early indicator that this new therapy can potentially reach broader populations in need. Ultimately, the rigor of comparative effectiveness outcome analysis will be needed to inform on the value of introducing a personalized regenerative strategy in heart failure management.