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Original Investigation |

Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy:  The TAC-HFT Randomized Trial

Alan W. Heldman, MD1,2; Darcy L. DiFede, RN, BSN1; Joel E. Fishman, MD, PhD3; Juan P. Zambrano, MD1,2; Barry H. Trachtenberg, MD1,2; Vasileios Karantalis, MD1; Muzammil Mushtaq, MD1,2; Adam R. Williams, MD1,4; Viky Y. Suncion, MD1; Ian K. McNiece, PhD1,2,8; Eduard Ghersin, MD3; Victor Soto, MD1,2; Gustavo Lopera, MD1,2,5; Roberto Miki, MD2; Howard Willens, MD2; Robert Hendel, MD2; Raul Mitrani, MD2; Pradip Pattany, PhD; Gary Feigenbaum, MD1,2; Behzad Oskouei, MD1,2; John Byrnes, MD1,2; Maureen H. Lowery, MD2; Julio Sierra, MD1; Mariesty V. Pujol, MBA1; Cindy Delgado, MA1; Phillip J. Gonzalez, CRC1; Jose E. Rodriguez, RTMR1; Luiza Lima Bagno, PhD1; Didier Rouy, MD, PhD6; Peter Altman, PhD6; Cheryl Wong Po Foo, PhD6; Jose da Silva, PhD1; Erica Anderson, MA7; Richard Schwarz, PhD1; Adam Mendizabal, PhDc7; Joshua M. Hare, MD1,2
[+] Author Affiliations
1The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine
2Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
3Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida
4Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
5Miami Veterans Affairs Healthcare System, Miami, Florida
6Biocardia Corporation, San Carlos, California
7EMMES Corporation, Rockville, Maryland
8MD Anderson Cancer Center, Houston, Texas.
JAMA. 2014;311(1):62-73. doi:10.1001/jama.2013.282909.
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Importance  Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial.

Objective  To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy.

Design, Setting, and Patients  A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up.

Interventions  Injections in 10 LV sites with an infusion catheter.

Main Outcomes and Measures  Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias.

Results  No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (−6.3; 95% CI, −15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (−8.2; 95% CI, −17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, −9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (−18.9%; 95% CI, −30.4 to −7.4; within-group, P = .004) but not by BMCs (−7.0%; 95% CI, −15.7% to 1.7%; within-group, P = .11) or placebo (−5.2%; 95% CI, −16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (−4.9; 95% CI, −13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (−2.1; 95% CI, −5.5 to 1.3; P = .21) or placebo (−0.03; 95% CI, −1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change.

Conclusions and Relevance  Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach.

Trial Registration  clinicaltrials.gov Identifier: NCT00768066

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Figures

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Figure 1.
Study Flow Chart
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Figure 2.
Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on the 6-Minute Walk Distance

Patients in the mesenchymal stem cell group exhibited a significant increase in 6-minute walk distance when 6-month and 12-month time points were compared to baseline in a repeated measures model (P = .03). No significant difference was observed for patients in the bone marrow cell group (P = .73) or in the placebo group (P = .25). Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P<.05.bWithin group, P<.01.

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Figure 3.
Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on Minnesota Living With Heart Failure Score

Minnesota Living With Heart Failure questionnaire score improved in a repeated measures analysis of variance compared with baseline for the mesenchymal stem cell group (P = .02) and the bone marrow group (P = .005) but not the placebo group (P = .38). Repeated measures analyses of variance for model P values: treatment group, P = .29; time, P = .01; treatment group × time, P = .71. Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin-group, P<.05.bWithin-group, P<.01.

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Figure 4.
Percent Change in Scar Size as a Percentage of Left Ventricular Mass

The 14 patients treated with mesenchymal stem cells (MSCs) exhibited a significant reduction in scar size (P = .004) as a percentage of left ventricular mass with no differences for the 15 patients treated with bone marrow cells or the 16 patients in the placebo group. The overall analysis of variance was P=.13. Data markers represent means; error bars, 95% CIs.aWithin group, P<.01.

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Figure 5.
Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on the Scar Size

Significant reduction in scar size as the percentage of left ventricular mass for patients treated with mesenchymal stem cells (MSCs) and those in the placebo group who underwent serial magnetic resonance imaging. Repeated measures of analysis of variance model P values: treatment group, P=.99; time, P=.007; treatment group × time, P=.22. Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.aWithin group, P<.05 vs baseline.bWithin group, P<.01 vs baseline.

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Figure 6.
Cardiac Magnetic Resonance Images From a Representative Patient Before and 12 Months After Mesenchymal Stem Cell 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 depicted 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 from 30.85 g at baseline to 21.17 g at 12 months. 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 mesenchymal stem cells, the delayed tissue enhancement receded in the midinferior and basal anterior walls (see Interactive of representative cardiac MRI cine sequences).

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