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
N1 - Funding Information:
The authors thank Adrian Glenn, Hao Zeng, Miguel Huerta, Claudia Anchante, Julie Avalos and Stephen Taylor for their excellent technical and surgical support, Laura Smith for performing the MRI scans and performing preliminary MRI analyses, Kristen J. Nikula for pathological report, Jackelyn Valle for immunostaining and scanning, and Nina Duong for blood processing. Sources of Funding This work was partially supported by a grant to Capricor from NIH (HL103356). General laboratory support was provided by the Cedars-Sinai Board of Governors Heart Stem Cell Center and NIH. H.K. was supported, in part, by a fellowship from the Uehara Memorial Foundation and the Sumitomo Life Social Welfare Services Foundation.
Publisher Copyright:
© 2016 The Authors.
PY - 2016/2/1
Y1 - 2016/2/1
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
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U2 - 10.1161/JAHA.115.002796
DO - 10.1161/JAHA.115.002796
M3 - Article
C2 - 26857066
AN - SCOPUS:85002625474
SN - 2047-9980
VL - 5
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 2
M1 - e002796
ER -