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Clinical Trials, U.S.: Heart Disease
Clinical Trials, U.S.: Heart Disease
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Clinical Trials, U.S.: Heart Disease
Heart disease is consistently the leading cause of mortality in the United States. A range of pathologies can lead to heart disease, including chronic ischemia, hypertension, acute myocardial infarction (AMI), endocarditis, and congenital malformations; however, few standard treatments aside from cardiac transplantation address the fundamental loss of functional cardiomyocytes that occurs in many cases of heart disease.
Over the past 20 years, stem cell (SC) studies have gained significant attention due to their potential to generate functional cardiomyocytes. Although SC treatments for heart disease in the United States are currently only approved within clinical trials, Phase I/II results suggest that some SC treatments can help prevent, and even reverse, disease progression for clinically significant outcomes. In this review, clinical trials are organized by stem cell type; and within each type, current clinical indications, limitations, and treatment methods necessary to treat heart disease are discussed.
Clinical Trials of Skeletal Myoblast–SC Treatments for Heart Disease
Adult skeletal myoblasts (SMs) were the first type of SC therapy used to treat heart disease. These cells harbor precursor cells, called satellite cells, which have regenerative potential due in part to their characteristic expression of PAX3 and PAX7, without expression of CSPG4. In normal skeletal muscle, these cells quiescently exist, but with injury, signals cause them to proliferate, forming multinucleated myotubes. Studies suggest that this process also occurs when SMs are introduced to injured cardiac muscle. Clinical trials of SMs have extensively explored their use to treat congestive heart failure (CHF). SM treatments are commonly autologous, and harvested SMs are abundantly available, easy to proliferate in culture, and relatively more resistant to ischemic conditions than cardiac cells. Despite this potential, clinical trials have not resulted in clinically significant improvements for heart disease. The MARVEL trial at Duke University demonstrated that in patients with severe CHF and ejection fraction (EF) < 35 percent, no significant improvement resulted in functional capacity analyzed by the walk test and the Minnesota Living With Heart Failure Score after intramyocardial-SM injections. In the U.S.-collaborated SEISMIC trial, no significant difference in global left ventricular (LV)-EF resulted between patients with low, high, or placebo-dose SM treatments after 6 months, as verified by multigated acquisition scans. Importantly, several studies demonstrate that SMs do not form electromechanical connections with surrounding cardiomyocytes due to their inability to express connexin 43. Consequently, several clinical trials have demonstrated adverse events such as ventricular tachyarrhythmia.
Bone Marrow–SC Treatments for Heart Failure
Adult bone marrow (BM) includes several cell types, including hematopoietic and non-hematopoietic SCs. Hematopoietic stem cells can generate red blood cells, lymphocytes, neutrophils, monocytes, and other mononuclear SCs. Together, hematopoietic SCs are called BM-mononuclear cells (BM-MNCs). A majority of BM-MNCs clinical trials use autologous transplantation; however, the FOCUS-CCTRN trial at the Texas Heart Institute demonstrated limitations of autologous treatments in patients with chronic diseases and elderly age.
To improve these limitations, other trials demonstrated that extracorporeal shock wave increases chemokines and other factors that improve BM-MNC retention among cardiomyocytes. Some studies suggest that when administered to patients, BM-MNCs fuse with recipient cardiomyocytes, or release biologically active factors that stimulate recipient cardiac SCs to proliferate. In contrast to other types of SCs, the 2004 C. E. Murry et al. clinical trial published in Nature demonstrated that BM-MNCs themselves do not transdifferentiate into functional cardiomyocytes.
Some BM-MNC trials indicate improvement in ischemic heart disease (IHD). The TIME and LateTIME trials at the Minneapolis Heart Institute found no significant improvement in global or regional LV function, or in wall motion changes of the post-AMI zone, at six months after autologous intracoronary BM-MNC treatment administered three to seven days post-AMI. However, other studies suggest that long-term follow-up and designation of new endpoints may reveal previously hidden benefits of BN-MNC treatment. The U.S.-collaborated REPAIR-AMI trial showed a sustained average improvement in LVEF of 8 percent at 5 years and a reduction of post-AMI size by 5.5 percent at four months, and retrospective analysis demonstrated that the optimal time of intracoronary treatment was five to seven days post-AMI.
Mesenchymal SC Treatments for Heart Disease
Non-hematopoietic SCs in adult BM are called stromal or mesenchymal cells. Mesenchymal stem cells (MSCs) have the capacity for self-renewal and multi-lineage differentiation to generate bone, cartilage, fibrous connective tissue, even myocytes. Although MSCs represent only 1 percent of nucleated cells in BM, in vitro culture expansion can successfully generate sufficient cells for timely therapeutic potential, and harvest of MSCs from other sources, such as adipose tissue and even allogenic sources, is also possible. To treat heart disease, MSCs demonstrate promise to graft into a variety of cell types, including vascular smooth muscle and endothelial, which improve cardiovascular function through neovascularization, secretion of growth factors, cytokines, and other signaling molecules. Transdifferention has been shown to occur both in vitro to cardiomyocytes as well as in vivo to cardiomyocytes when among naïve cardiomyocytes.
Several MSC-therapy clinical trials, including the TAC-HFT trial at the University of Miami, also found results of improved LV function, as well as reverse ischemic remodeling and decreased post-AMI size. The POSEIDON trial at the University of Miami established MSCs’ autologous and allogenic safety and efficacy in treatment of early-stage IHD, and found that patients who received low-dose treatment of MSCs (20 million cells) presented with the most favorable reductions in LV volume and increased EF. Clinical trials for autologous adipose-derived MSCs have not begun in the United States but show promise internationally, such as in the APOLLO trial.
Embryonic Stem Cell Treatments for Heart Disease
Human embryonic stem cells (hESCs) are omnipotent or pluripotent cells derived from pre-implantation-stage embryos. These cells have been intensively investigated for their potential use in cardiac regeneration, and several pre-clinical trials have found that hESCs differentiate into contractile cardiomyocytes in vitro. Clinical application of hESCs is controversial due to ethical issues, immunological incompatibility, and risk of teratoma formation. As of 2014, no U.S. clinical trials with hECSs have begun.
Induced Pluripotent SC Treatments for Heart Disease
As late as 2006, Shinya Yamanaka discovered that adult somatic cells can be induced by pluripotency transcription factors to form induced pluripotent stem cells (iPSCs). iPSCs have the potential to be therapeutically useful, but many technical issues must first be resolved that will require a better understanding of their biology. As of 2014, no U.S. clinical trials with iPSCs have begun.
Cardiac SC and Cardiosphere-Derived Treatments for Heart Disease
The adult heart contains cardiac stem cells (CSCs) that express the unique surface receptor tyrosine kinase c-kit as well as other markers, such as Sca-1, and Isl-1. These cells are self-renewing, clonogenic, and multipotent, which allows them to differentiate into myocytes, vascular smooth muscle, and endothelial cells. CSCs are harvested via a minimally invasive biopsy or during cardiac surgery, isolated from others cells by markers, expanded in vitro, and can be frozen for subsequent use.
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