Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review

Abstract

Importance: Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice.

Objective: To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date.

Evidence review: Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 26, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review.

Findings: Although adult stem cells were once believed to have the ability to create new heart tissue, preclinical studies suggest that these cells release cardioprotective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized clinical trials, most of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methods, discrepancies in reporting, and an overreliance on surrogate end points.

Conclusions and relevance: Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.

Figure 1. Schematic of the proposed mechanism of action of stem cell therapy

The figure illustrates the theoretical mechanisms of action of various stem cell populations proposed in the literature. Although stem cells can potentially repair the injured myocardium by increasing angiogenesis, releasing factors that reduce cell death or modulate the immune system (e.g., paracrine activation), and/or creating new heart tissue, thus far only paracrine activation has been proven while the other hypotheses remain controversial. Stem cell sources include: 1) the bone marrow which contains the most diverse group of cells (e.g., HSCs, EPCs, MSCs, and specific stromal cell subpopulations) and factors (e.g., cytokine and growth factors) that can potentially regenerate the myocardium; 2) other sources of MSCs such as adipose tissue and the umbilical cord; and 3) cardiac tissue that may contain cardiac progenitor cells or cardiospheres. HSCs: hematopoietic stem cells, EPCs: endothelial progenitor cells, BM: bone marrow, SCs: stem cells, GFs: growth factors, MSCs: mesenchymal stem cells, CSCs: cardiac stem cells, CDCs: cardiosphere-derived cells.

Figure 2. Overview of the various patient cohorts, cell types, doses, routes of delivery, and clinical endpoints used in adult stem cell trials

A significant difference in efficacy has been observed in earlier randomized, controlled trials versus later randomized, controlled trials, which may be partially explained by variations in patient cohorts, cell types, doses, routes of delivery, and clinical endpoints evaluated in adult stem cell trials. Trials have been conducted in patients with various cardiac diseases including AMI, chronic ischemia/angina, ischemic CM, and non-ischemic CM. Within each cohort, certain patient characteristics may also affect efficacy such as transplanting bone marrow acquired from young versus old patients, delivering cells to patients immediately versus weeks/months post MI, and treating patients who have suffered small versus large infarct or who have mild (<45%) versus significant (<35%) impairment in LVEF. Various adult stem cell types have also been evaluated, including bone-marrow derived cells (e.g., BMMNCs, CD34⁺ or CD133⁺ cells, and MSCs) and adipose/umbilical derived SCs, as well as stem cells derived from cardiac tissue (e.g., CSCs and CDCs). These cells have been delivered in multiple doses and with different delivery approaches. Finally, most studies have used surrogate endpoints like LVEF, infarct size, and perfusion defects, which do not always correlate with more definite endpoints such as death, myocardial infarction, revascularization, heart failure readmission, and other major adverse cardiovascular events (MACE).