Durable benefits of cellular postconditioning: Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction

Hideaki Kanazawa, Eleni Tseliou, James F. Dawkins, Geoffrey De Couto, Romain Gallet, Konstantinos Malliaras, Kristine Yee, Michelle Kreke, Ileana Valle, Rachel R. Smith, Ryan C. Middleton, Chak Sum Ho, Rohan Dharmakumar, Debiao Li, Raj R. Makkar, Keiichi Fukuda, Linda Marbán, Eduardo Marbán

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background--Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies. Methods and Results--Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDCtreated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Conclusions--Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.

Original languageEnglish
Article numbere002796
JournalJournal of the American Heart Association
Volume5
Issue number2
DOIs
Publication statusPublished - 2016

Fingerprint

Reperfusion
Swine
Myocardial Infarction
Centers for Disease Control and Prevention (U.S.)
Cicatrix
Magnetic Resonance Imaging
Miniature Swine
Balloon Occlusion
Cell- and Tissue-Based Therapy
Cardiac Myocytes
Hypertrophy
Collagen
Therapeutics
Macrophages
Placebos

Keywords

  • Allogeneic transplantation
  • Cardioprotective effect
  • Cardiosphere-derived cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Durable benefits of cellular postconditioning : Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction. / Kanazawa, Hideaki; Tseliou, Eleni; Dawkins, James F.; De Couto, Geoffrey; Gallet, Romain; Malliaras, Konstantinos; Yee, Kristine; Kreke, Michelle; Valle, Ileana; Smith, Rachel R.; Middleton, Ryan C.; Ho, Chak Sum; Dharmakumar, Rohan; Li, Debiao; Makkar, Raj R.; Fukuda, Keiichi; Marbán, Linda; Marbán, Eduardo.

In: Journal of the American Heart Association, Vol. 5, No. 2, e002796, 2016.

Research output: Contribution to journalArticle

Kanazawa, H, Tseliou, E, Dawkins, JF, De Couto, G, Gallet, R, Malliaras, K, Yee, K, Kreke, M, Valle, I, Smith, RR, Middleton, RC, Ho, CS, Dharmakumar, R, Li, D, Makkar, RR, Fukuda, K, Marbán, L & Marbán, E 2016, 'Durable benefits of cellular postconditioning: Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction', Journal of the American Heart Association, vol. 5, no. 2, e002796. https://doi.org/10.1161/JAHA.115.002796
Kanazawa, Hideaki ; Tseliou, Eleni ; Dawkins, James F. ; De Couto, Geoffrey ; Gallet, Romain ; Malliaras, Konstantinos ; Yee, Kristine ; Kreke, Michelle ; Valle, Ileana ; Smith, Rachel R. ; Middleton, Ryan C. ; Ho, Chak Sum ; Dharmakumar, Rohan ; Li, Debiao ; Makkar, Raj R. ; Fukuda, Keiichi ; Marbán, Linda ; Marbán, Eduardo. / Durable benefits of cellular postconditioning : Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction. In: Journal of the American Heart Association. 2016 ; Vol. 5, No. 2.
@article{9f89c1e03aa4460da2165c88638b47b0,
title = "Durable benefits of cellular postconditioning: Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction",
abstract = "Background--Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies. Methods and Results--Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDCtreated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Conclusions--Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.",
keywords = "Allogeneic transplantation, Cardioprotective effect, Cardiosphere-derived cells",
author = "Hideaki Kanazawa and Eleni Tseliou and Dawkins, {James F.} and {De Couto}, Geoffrey and Romain Gallet and Konstantinos Malliaras and Kristine Yee and Michelle Kreke and Ileana Valle and Smith, {Rachel R.} and Middleton, {Ryan C.} and Ho, {Chak Sum} and Rohan Dharmakumar and Debiao Li and Makkar, {Raj R.} and Keiichi Fukuda and Linda Marb{\'a}n and Eduardo Marb{\'a}n",
year = "2016",
doi = "10.1161/JAHA.115.002796",
language = "English",
volume = "5",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Durable benefits of cellular postconditioning

T2 - Long-term effects of allogeneic cardiosphere-derived cells infused after reperfusion in pigs with acute myocardial infarction

AU - Kanazawa, Hideaki

AU - Tseliou, Eleni

AU - Dawkins, James F.

AU - De Couto, Geoffrey

AU - Gallet, Romain

AU - Malliaras, Konstantinos

AU - Yee, Kristine

AU - Kreke, Michelle

AU - Valle, Ileana

AU - Smith, Rachel R.

AU - Middleton, Ryan C.

AU - Ho, Chak Sum

AU - Dharmakumar, Rohan

AU - Li, Debiao

AU - Makkar, Raj R.

AU - Fukuda, Keiichi

AU - Marbán, Linda

AU - Marbán, Eduardo

PY - 2016

Y1 - 2016

N2 - Background--Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies. Methods and Results--Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDCtreated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Conclusions--Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.

AB - Background--Infusion of allogeneic cardiosphere-derived cells (allo-CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long-term effects of allo-CDCs have not been assessed. We performed a placebo-controlled pivotal study for long-term evaluation, as well as shorter-term mechanistic studies. Methods and Results--Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo-CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC-treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo-CDC infusion. In addition, allo-CDCs improved regional function and decreased hypertrophy 2 months post-treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo-CDCtreated pigs at 2 months. Allo-CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short-term experiments designed to probe mechanism revealed antiapoptotic effects of allo-CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Conclusions--Allo-CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.

KW - Allogeneic transplantation

KW - Cardioprotective effect

KW - Cardiosphere-derived cells

UR - http://www.scopus.com/inward/record.url?scp=85002625474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85002625474&partnerID=8YFLogxK

U2 - 10.1161/JAHA.115.002796

DO - 10.1161/JAHA.115.002796

M3 - Article

C2 - 26857066

AN - SCOPUS:85002625474

VL - 5

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 2

M1 - e002796

ER -