Angela C. Rieger

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Rationale: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. Objective: To compare the safety and efficacy of 2 doses of allogeneic bone marrow–derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. Methods and Results: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by −6.4 g (interquartile range, −13.5 to −3.4 g; P=0.001) and 100 million by −6.1 g (interquartile range, −8.1 to −4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (−0.07 log pg/mL; 95% CI, −0.36 to 0.23; P=0.65; between group P=0.07). Conclusions: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

New insights into cell-based therapy for heart failure from the CHART-1 study

Cardiopoietic cells (C3BS-CQR-1) are bone marrow mesenchymal stem cells (MSCs) that have been pre-treated with a cocktail of factors: transforming growth factor-β1, fibroblast growth factor-2, insulin-like growth factor-1, activin-A, retinoic acid, α-thrombin, bone morphogenetic protein 4, and interleukin-6. The preconditioning of MSCs with these factors guides them towards a cardiogenic oriented cell type. These cells were tested in a large, multicentre, phase I, randomized clinical trial: Cardiopoietic stem Cell therapy in heart failURE (C-CURE).2 The results of this trial showed no treatment-associated adverse events or systemic toxicity. Moreover, superior improvements in cardiac function and physical performance measures were reported in the MSC-preconditioned group compared to standard of care alone.2 The promising results from C-CURE led to the largest phase II/III, cardiac stem cell trial to date: the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study, which evaluated the safety and efficacy of autologous cardiopoietic cell therapy in patients with ischaemic heart failure.3

Insights Into Signaling in Cell-Based Therapy for Heart Disease

Over the past several decades, stem cell therapy for heart disease has been translated from the bench to the bedside and in clinical trials improves cardiac structure and function in both ischemic and nonischemic cardiac disease. Although the regenerative effects of stem cells in cardiac disease are mediated by both paracrine and cell-to-cell contact mechanisms, many of the downstream signaling pathways remain to be fully elucidated. This review outlines what is currently known about the main signaling pathways involved in mesenchymal stem cell and cardiac stem cell survival, proliferation, and migration and mechanisms of action to repair the damaged heart.