Idiopathic dilated cardiomyopathy (IDCM) is a leading cause of congestive heart failure, produces death and disability via heart failure and sudden cardiac death, and accounts for ~50% of heart transplants performed. As such this disorder is a lead candidate for cell-based therapy. The primary phenotype of dilated cardiomyopathy is an enlarged, remodeled ventricle with increases in end-diastolic and end-systolic volumes, reduced ejection fraction, and impaired contractile and diastolic function. Cell-based therapy holds great promise as a new approach to produce durable and sustainable improvements in dysfunctional hearts and to cause reverse remodeling. If these effects can be clinically established and optimized, there is enormous potential for improving clinical outcomes for the many patients suffering from dilated cardiomyopathy. Our group has extensive experience with catheter delivery of bone-marrow derived mesenchymal stem cells in patients with ischemic cardiomyopathy and is now poised to test this exciting clinical hypothesis in patients with non-ischemic cardiomyopathy. There is substantial scientific and public interest for cardiac regenerative cell therapy strategies, based on pre-clinical, translational, and early clinical studies. This trial is currently approved by the FDA under investigator initiated IND number BB-14419 (PI: Hare), and is therefore ready to be initiated.
The specific aims of this proposal are: 1. To establish the safety and efficacy of bone marrow derived mesenchymal stem cell (MSC) therapy for patients with idiopathic dilated cardiomyopathy. We will perform a randomized comparison of autologous and allogeneic MSC therapy employing percutaneous delivery with a transendocardial catheter delivery system. 2. To compare two different bone marrow preparations - allogeneic vs. autologous bone marrow derived mesenchymal stem cells (MSCs) - for safety and efficacy in patients with non-ischemic cardiomyopathy. The mechanism of action at a phenotypic level will be assessed using cardiac magnetic resonance imaging (MRI) to measure MI size, regional and global LV function, tissue fibrosis, and tissue perfusion. A post-hoc analysis will be performed to test the hypothesis that in vitro assessments of cell morphology, cell surface markers, and cell colony growth potential may predict the ability of an individual patient's cells to improve the cardiac measures. 3. To assess cellular mechanisms of action of MSC therapy by measuring the capacity for endogenous cardiac stem cell proliferation and differentiation. Endomyocardial biopsies will be obtained from the patients enrolled in this trial and tested for their capacity to yield endogenous cardiac stem cells.

Public Health Relevance

This clinical study will address a significant clinical need, namely the investigation of new and promising therapies for heart failure, one of the leading causes of cardiovascular death and disability. The proposed studies will elucidate new mechanisms of repair and regeneration of heart tissue.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Buxton, Denis B
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University of Miami School of Medicine
Internal Medicine/Medicine
Schools of Medicine
Coral Gables
United States
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Tompkins, Bryon A; Natsumeda, Makoto; Balkan, Wayne et al. (2017) What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction. Circ Res 120:252-255
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Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi et al. (2017) Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure. Proc Natl Acad Sci U S A 114:12033-12038
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Hatzistergos, Konstantinos E; Hare, Joshua M (2016) Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart. Circ Res 118:382-7
Hatzistergos, Konstantinos E; Saur, Dieter; Seidler, Barbara et al. (2016) Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circ Res 119:921-30
Florea, Victoria; Balkan, Wayne; Schulman, Ivonne Hernandez et al. (2016) Cell Therapy Augments Myocardial Perfusion and Improves Quality of Life in Patients With Refractory Angina. Circ Res 118:911-5

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