Resumen de Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy The TAC-HFT Randomized Trial
Alan W. Heldman, Darcy L. DiFede, Joel E. Fishman, Juan P. Zambrano, Barry H. Trachtenberg
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 Recent preclinical studies and clinical trials suggest that bone marrow–derived cell preparations, including mononuclear bone marrow cells1- 6 and mesenchymal stem cells,7,8 ameliorate left ventricular (LV) remodeling with acute4,7 myocardial infarction (MI) and chronic1- 3,5,8,9 ischemic cardiomyopathy. An effective antiremodeling, proregenerative treatment for ischemic cardiomyopathy would address a major unmet need for many patients. By virtue of their greater differentiation potential,10 the culture-expanded mesenchymal stem cells constituent of bone marrow is speculated to have potential for forming ectopic tissue11 or stimulating tumors12 but could also have greater antifibrotic and proregenerative effects than bone marrow mononuclear cells.13 An unresolved issue is whether mesenchymal stem cells have similar safety and possibly greater efficacy than bone marrow mononuclear cells.8 To address these issues, we performed a phase 1 and 2 randomized, double-blind, placebo-controlled study of autologous culture–expanded mesenchymal stem cells vs autologous bone marrow mononuclear cells delivered by transendocardial stem cell injection (TESI) in patients with ischemic cardiomyopathy.14 The findings of the Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial (TAC-HFT) have implications for the development of cell-based therapies for ischemic cardiomyopathy and possibly for other organs and diseases.
