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Review
. 2018 Jul 6;123(2):266-287.
doi: 10.1161/CIRCRESAHA.118.311217.

Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions

Affiliations
Review

Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions

Monisha N Banerjee et al. Circ Res. .

Abstract

Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products.

Keywords: cell- and tissue-based therapy; clinical trial; heart diseases; heart failure.

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Figures

Figure 1.
Figure 1.. Modes of stem cell delivery.
A) Intravenous delivery (peripheral veins not shown). B) Transendocardial injection (TESI) via catheter. C) Epicardial injection. D) Intracoronary infusion via catheter. Reproduced with permission from .
Figure 2.
Figure 2.. LV remodeling and potential targets for stem cell therapy.
After an initial ischemic insult, the resulting necrosis, extracellular matrix (ECM) turnover and collagen breakdown promotes homing of inflammatory cells. Cardiomyocyte death forces the remaining cells to work harder to maintain cardiac output. The resulting cardiomyocyte hypertrophy, ECM remodeling and fibrosis produce wall thinning, increased wall stress, ventricular dilation (remodeling) and impaired function. The overworked cardiomyocytes exhibit mitochondrial dysfunction, oxidative stress and impaired Ca2+ handling. Stem cells release paracrine mediators and directly differentiate into cardiomyocytes, inhibit cardiomyocyte apoptosis and inflammation, promote angiogenesis and stimulate endogenous cardiac stem cells. Together, these stem cell effects contribute to reversing/attenuating remodeling. (Illustration credit: Ben Smith).
Figure 3.
Figure 3.. Advances in cardioregenerative medicine.
First generation stem cell therapy utilized skeletal myoblasts, heterogeneous populations of cells, such as BMMNCs and ADRCs, and more purified MSCs and hematopoietic stem cells (CD134+/CD133+) isolated from either bone marrow or blood. Second generation stem cells include purified cardiac cell populations such as ckit+ CSCs and CDCs, pluripotent cells (ESCs and iPSCs) and allogeneic cells. Next generation stem cells include modified, lineage-directed stem cells such as cardiopoietic stem cells derived from MSCs. BMMNCs = bone marrow mononuclear cells; ADRCs = adipose-derived regenerative cells; MSCs = mesenchymal stem cell; CSC = cardiac stem cell; CDC = cardiosphere-derived cell; ESC = embryonic stem cell; iPSC = induced pluripotent stem cell. (Illustration credit: Ben Smith).
Figure 4.
Figure 4.. Scar size reduction in a TAC-HFT trial patient.
Cardiac Magnetic Resonance Images from a representative patient before and 12 months after MSC Injection. A) Short-axis views of the basal area of a patient’s heart, with delayed tissue enhancement delineated at the septal wall. Delayed tissue enhancement corresponds to scarred tissue and is brighter than the nonscarred tissue (automatically detected and delineated with red using the full width at half maximum technique). The red, green, and white lines demarcating the endocardial, epicardial contours, and borders of the segments, respectively, were drawn manually. Twelve months after injection of mesenchymal stem cells, scar mass was reduced significantly. B) Long-axis 2-chamber views of the same heart with delayed tissue enhancement delineated at the anterior and inferior wall, as well as the entire apex. At baseline and at 12 months after injection of MSCs, the delayed tissue enhancement receded in the midinferior and basal anterior walls. Reproduced with permission from .
Figure 5.
Figure 5.. Results from the SCIPIO trial.
A) confocal image of autologous cardiac stem cells used in this study demonstrating c-kit positivity (green). Nuclei are stained blue (DAPI) B) LVEF (measured by echocardiography) at 4-month follow-up and baseline in control and treated patients. C) LVEF at 4 and 12 months post-treatment in 8 CSC treated patients. D) Absolute change in LVEF from baseline at 4 and 12 months in the treated patients. Modified and reproduced with permission from.
Figure 6.
Figure 6.
Ejection Fraction improvement in a patient from the POSEIDON-DCM trial. A, Cardiac computed tomography shows decreased global EF at baseline. B, Global EF has significantly improved at 12-months post TESI of MSCs. ED indicates end diastolic; EDV, end diastolic volume; ES, end systolic; ESV, end systolic volume; LVEF, left ventricular ejection fraction; MSC, mesenchymal stem cell; and TESI, Transendocardial Stem Cell Injection. Reprinted from Hare et al132 with permission. Copyright ©2017, Elsevier.

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