Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling

Adam R. Williams, Viky Y. Suncion, Frederic McCall, Danny Guerra, Jacques Mather, Juan P. Zambrano, Alan W. Heldman, Joshua Hare

Research output: Contribution to journalArticle

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. Methods and 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). Conclusion-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.

Original languageEnglish
Article numbere000140
JournalJournal of the American Heart Association
Volume2
Issue number3
DOIs
StatePublished - Sep 4 2013

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Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Cicatrix
Injections
Heart Ventricles
Cardiomyopathies
Swine
Myocardial Infarction
Magnetic Resonance Imaging
Ventricular Remodeling
Magnetic Resonance Angiography
Catheterization
Dilatation
Anatomy
Coronary Vessels
Theoretical Models
Clinical Trials

Keywords

  • Cardiac magnetic resonance imaging
  • Ischemic cardiomyopathy
  • Stem cell therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. / Williams, Adam R.; Suncion, Viky Y.; McCall, Frederic; Guerra, Danny; Mather, Jacques; Zambrano, Juan P.; Heldman, Alan W.; Hare, Joshua.

In: Journal of the American Heart Association, Vol. 2, No. 3, e000140, 04.09.2013.

Research output: Contribution to journalArticle

Williams, Adam R. ; Suncion, Viky Y. ; McCall, Frederic ; Guerra, Danny ; Mather, Jacques ; Zambrano, Juan P. ; Heldman, Alan W. ; Hare, Joshua. / Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. In: Journal of the American Heart Association. 2013 ; Vol. 2, No. 3.
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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. Methods and 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). Conclusion-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.",
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AU - Williams, Adam R.

AU - Suncion, Viky Y.

AU - McCall, Frederic

AU - Guerra, Danny

AU - Mather, Jacques

AU - Zambrano, Juan P.

AU - Heldman, Alan W.

AU - Hare, Joshua

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N2 - 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. Methods and 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). Conclusion-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.

AB - 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. Methods and 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). Conclusion-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.

KW - Cardiac magnetic resonance imaging

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