title: Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling.
abstract: BACKGROUND
  Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy.
  
  
  RESULTS
  Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post-MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3-dimensional cardiac magnetic resonance imaging angiography-derived anatomy to accurately target infarct border zone injections. MSC-treated animals had a 19.62 ± 2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09 ± 2.31% from 3 to 6 months postinjection (P<0.0001). MSC-treated animals had unchanged end-diastolic volume (EDV; P=0.08) and end-systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC-treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69 ± 1.68% to 35.85 ± 2.74% at 3 months post-MSC injection and progressed to 39.02 ± 2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow-up (P=0.33).
  
  
  CONCLUSIONS
  Intramyocardial injection of allogeneic MSCs leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials.
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Williams
authors.forename: Viky Y
authors.initials: VY
authors.lastname: Suncion
authors.forename: Frederic
authors.initials: F
authors.lastname: McCall
authors.forename: Danny
authors.initials: D
authors.lastname: Guerra
authors.forename: Jacques
authors.initials: J
authors.lastname: Mather
authors.forename: Juan P
authors.initials: JP
authors.lastname: Zambrano
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D005260:Female; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D013552:Swine; D013556:Swine, Miniature; D020257:Ventricular Remodeling
keywords: cardiac magnetic resonance imaging; ischemic cardiomyopathy; stem cell therapy