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Circ Res. 2014 Apr 11;114(8):1302-10. doi: 10.1161/CIRCRESAHA.114.303180. Epub 2014 Feb 24.

Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.

Author information

1
From the University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL (V.K., D.L.D., R.S., M.M., V.Y.S., A.W.L., J.M.H.); Johns Hopkins University, Cardiovascular Division, Baltimore, MD (G.G., S.S., E.B., J.D.-S., A.C.L.); University of Maryland, Cardiothoracic Surgery, Baltimore, MD (S.P., J.C.); Veterans Affairs Healthcare System, Cardiothoracic Surgery, Miami, FL (J.S., T.Z.K.); Jackson Health System, Cardiology, Miami, FL (J.P.Z.); University of Miami Miller School of Medicine, Radiology, Miami, FL (J.F., P.P.); University of Texas MD Anderson, Stem Cell Transplantation, Houston, TX (I.M.N.), Johns Hopkins University, Heart and Vascular Institute, Baltimore, MD (K.W.), Johns Hopkins University, Comprehensive Transplant Center (A.S.); University of Southern California, Internal Medicine, Los Angeles, CA (G.F.); Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (I.B.); EMMES Corporation, Rockville, MD (A.M.), University of Miami Miller School of Medicine, Hematology/Oncology, Miami, FL (J.B.); and University of Miami Miller School of Medicine, Cardiology, Miami, FL (T.Z.K., M.L.).

Abstract

RATIONALE:

Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.

OBJECTIVE:

To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.

METHODS AND RESULTS:

Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).

CONCLUSIONS:

Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.

CLINICAL TRIAL REGISTRATION URL:

http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

KEYWORDS:

coronary artery bypass; mesenchymal stromal cells; stem cell

PMID:
24565698
PMCID:
PMC4104798
DOI:
10.1161/CIRCRESAHA.114.303180
[Indexed for MEDLINE]
Free PMC Article

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