Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Antifibrotic Effects Post-TESI Short-axis sections of delayed enhancement cardiac magnetic resonance depict the infarct extension (scar = red with white arrows) before (A to C) and 3-months after (D to F) treatment and, as seen in comparable gross pathology sections (G to J), 3 months after transendocardial stem cell injection (TESI). (A, D) In this representative example, scar size changed from (A, D) 7.2 to 9.0 g for the placebo, (B, E) 9.7 to 5.9 g for autologous mesenchymal stem cells (MSCs) and (C, F) 8.9 to 5.8 g for c-kit+ cardiac stem cells (CSCs)/MSCs. (G) Cell-treated groups had similar scar size reduction (between-group comparison, 2-way analysis of variance [ANOVA] p < ) and (K) increased viable tissue (between-group comparison, 2-way ANOVA p = ). Graphs = mean ± SEM. *p < 0.05 within-group repeated measures 1-way ANOVA; 2-way ANOVA between-group comparison and Tukey's multicomparison test; **p < 0.05 CSC/MSC versus placebo at 1, 2, and 3 months post-TESI; and †p < 0.05 MSC versus placebo at 1, 2, and 3 months post-TESI. LV = left ventricular; MI = myocardial infarction. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc EF Improvement Post-TESI Change in ejection fraction (EF) for individual animals for (A) EF units and (B) as a percent change (p = 0.01) post-TESI. Accompanying this EF restoration was a substantial improvement in the CSC/MSC group in (C) stroke volume (p = 0.008) and (D) cardiac output, which increased only in the CSC/MSC group (p = 0.007). Graphs represent mean ± SEM. *p < way ANOVA, 3 months post-MI vs. 1, 2, and 3 months post TESI with CSC/MSC; **p < 0.05 CSC/MSC vs. placebo; †p < 0.05 CSC/MSC vs. MSCs. Abbreviations as in Figure 1. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Contractility and Diastolic Strain (A) Circumferential strain rate (peak Eulerian circumferential shortening strain [Ecc]) in the infarct zone improved in both cell- treated animal groups but not in the placebo group (*MSC p = 0.04; **CSC/MSC p < 0.004; between-group comparison p = 0.1). (B) Diastolic strain increased only in the combination-treated animals (*p = 0.04), remaining unchanged in the MSC (p = NS) and placebo (p = NS) groups (between-group comparison p = 0.9). Abbreviations as in Figure 1. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Endothelial Function Flow-mediated dilation improved endothelial function in both cell-treated groups. CSC/MSC vs. Placebo **p < 0.05; MSCs vs. placebo †p < Abbreviations as in Figure 1. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Treatment-Enhanced Myocardial Mitotic Activity Confocal microscopy depicts increased mitotic activity of endogenous cardiomyocytes (phospho-histone H3–positive [pHH3 + ] nuclei) in (A) border and (B) remote zones in cell-treated hearts at 3 months post-TESI. Based on the average number of pHH3 + mitotic cardiomyocytes per slide per group in the (C) infarct, (D) border, and (E) remote zones, combination cell therapy significantly increased mitotic activity in the border zone compared with placebo (*p = 0.05). According to the average number of pHH3 + mitotic cells within the myocardium per slide per group in the (F) infarct, (G) border, and (H) remote zones, combination therapy produced significant increases in mitotic cells in the infarct zone compared with placebo (*p = 0.05). DAPI = 4',6-diamidino- 2-phenylindole; other abbreviations as in Figure 1. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Infarct Zone Perfusion According to the contrast-enhanced cardiac magnetic resonance perfusion analysis in the resting state, there was a trend toward deterioration of tissue perfusion in the infarct zone with placebo (−15.0 ± 9.9%; *p = 0.07). This decline did not occur in the cell treatment groups (MSC −6.4 ± 12.2%, p = 0.32; c kit+ CSC/MSC 23.7 ± 22.5%, p = 0.72). Bar graphs depict change in tissue perfusion from 3 months post-MI and 3 months post-TESI as measured according to upslope analyses. Abbreviations as in Figure 1. Figure Legend:

Date of download: 6/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy J Am Coll Cardiol. 2015;66(18): doi: /j.jacc Combination Stem Cell Therapy for Heart Failure Tagged harmonic phase cardiac magnetic resonance strain maps show significantly depressed regional function according to peak Eulerian circumferential shortening strain (Ecc) at (A) 3 months post–myocardial infarction (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. (B) At 3 months after cell injection, infarct zone contractility has improved (less, red/white; more, green/blue). TESI = transendocardial stem cell injection. Figure Legend: