Bryon A. Tompkins

Global position paper on cardiovascular regenerative medicine

Authors/Task Force Members. Chairpersons: Francisco Fern andez-Avilés (Spain), Andre Terzic (USA); Basic Research Subcommittee: Lina Badimon (Spain), Kathleen Broughton (USA), Darcy L. DiFede (USA), Stefanie Dimmeler (Germany), Rosalinda Madonna (Italy), Marc S. Penn (USA), Mark A. Sussman (USA), Joost P.G. Sluijter (The Netherlands), Kai C. Wollert (Germany); Translational Research Subcommittee: Wayne Balkan (USA), Roberto Bolli (USA), Steven Chamuleau (The Netherlands), Dominique Charron (France),

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.

Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract Background Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair. Methods This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion. Results No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy. Conclusion Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder. Clinical Trial Registration www.clinicaltrials.gov: CRATUS (#NCT02065245).

What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction

Although therapy for cardiovascular disease has led to consistent annual declines in mortality, myocardial infarction still represents an irreversible injury to the myocardium leading to the substrate for heart failure and sudden cardiac death.1 Indeed, the extent of scar resulting from myocardial infarction is an important predictor of mortality.2 Even with timely coronary intervention, infarct size is a significant problem likely exacerbated by ischemia/reperfusion injury.3 Supported by preclinical studies, cell-based therapy has emerged as an attractive treatment for minimizing/reversing the effects of myocardial infarction in patients.4,5 Article, see p 324 Stem cell (SC) mobilization from the bone marrow to acutely injured tissue significantly enhancing wound healing was first observed in a mouse skin wound model.6 Large animal models demonstrated that SC therapy produces significant improvements in acute myocardial infarction (AMI),7,8 leading to clinical trials for SC therapy in patients with AMI and heart failure. Bone marrow–derived SC therapy for AMI is safe. Unfortunately, the hypoxic post-AMI environment is hostile to cardiomyocytes and migrating or introduced SCs, and this proapoptotic milieu may be the limiting factor clinically. However, a recent meta-analysis reported that patients with ischemic cardiomyopathy who received bone marrow–derived SCs exhibited improved left ventricular ejection fraction (LVEF) and reduced infarct size and remodeling (Table).9 View this table: Table 1. Randomized Control Trials Evaluating CD34+ Bone Marrow–Derived Stem Cell Therapy for Acute Myocardial Infarction Endothelial progenitor cells (EPCs) are bone marrow–derived mononuclear cells expressing both hematopoietic SC and endothelial cell markers. The prototypical EPC, selected on the basis of CD34 expression (CD34+), promotes neovascularization and regeneration.13 The neovascular effects were demonstrated in a Phase I/II trial, where CD34+ EPCs administered to patients with refractory angina pectoris, decreased the frequency of events, and increased exercise tolerance as compared to placebo-treated patients. …

Cardiac surgery for Chagas disease

Although Chagas disease is a rare entity in North America, it is associated with significant cardiac morbidity. It is estimated that 20‐30% of those who are infected will eventually develop cardiovascular disease secondary to Chagas disease. We review the literature and share our experience on the surgical management of this challenging patient population.

Preclinical Studies of Stem Cell Therapy for Heart Disease

As part of the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) series to enhance regenerative medicine, here, we discuss the role of preclinical studies designed to advance stem cell therapies for cardiovascular disease. The quality of this research has improved over the past 10 to 15 years and overall indicates that cell therapy promotes cardiac repair. However, many issues remain, including inability to provide complete cardiac recovery. Recent studies question the need for intact cells suggesting that harnessing what the cells release is the solution. Our contribution describes important breakthroughs and current directions in a cell-based approach to alleviating cardiovascular disease.

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

Perspectives on the Evolution of Stem Cell Therapy for Heart Failure.

The advent of stem cell and cell-based therapy has opened the door to a non-pharmacological treatment of heart failure (HF). This exciting opportunity is at an early stage and many issues regarding optimization of this approach remain. A variety of stem cells (SCs), doses, and delivery methods are being tested in clinical trials, supporting the conclusion that there is still “no consensus on … which cell type to transplant, to improve efficacy and safety” (Silvestre and Menasche, 2015). To provide a guide going forward, Silvestre and Menasche take us through the evolution of the therapeutic use of SCs for heart failure (Silvestre and Menasche, 2015). Their main proposal is that “cardiac-committed cells” in general and “pluripotent stem cell-derived cardiac progenitors” in particular are “particularly attractive” candidates for cell therapy.

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.