Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction
BackgroundInfusion 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...
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| Format: | Article |
| Language: | English |
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Wiley
2016-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.115.002796 |
| _version_ | 1818398646267281408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hideaki Kanazawa |
| collection | DOAJ |
| description | BackgroundInfusion 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 ResultsMinipigs 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‐CDC‐treated 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. ConclusionsAllo‐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. |
| first_indexed | 2024-12-14T07:08:05Z |
| format | Article |
| id | doaj.art-66e5dab1634247818be04a3dfdc81abe |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-14T07:08:05Z |
| publishDate | 2016-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-66e5dab1634247818be04a3dfdc81abe2022-12-21T23:12:03ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-02-015210.1161/JAHA.115.002796Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial InfarctionHideaki Kanazawa0Eleni Tseliou1James F. Dawkins2Geoffrey De Couto3Romain Gallet4Konstantinos Malliaras5Kristine Yee6Michelle Kreke7Ileana Valle8Rachel R. Smith9Ryan C. Middleton10Chak‐Sum Ho11Rohan Dharmakumar12Debiao Li13Raj R. Makkar14Keiichi Fukuda15Linda Marbán16Eduardo Marbán17Cedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACapricor Inc., Los Angeles, CACapricor Inc., Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CAGift of Life Michigan, Ann Arbor, MICedars‐Sinai Biomedical Imaging Research Institute, Los Angeles, CACedars‐Sinai Biomedical Imaging Research Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CADepartment of Cardiology, Keio University School of Medicine, Shinjuku Tokyo, JapanCedars‐Sinai Heart Institute, Los Angeles, CACedars‐Sinai Heart Institute, Los Angeles, CABackgroundInfusion 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 ResultsMinipigs 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‐CDC‐treated 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. ConclusionsAllo‐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.https://www.ahajournals.org/doi/10.1161/JAHA.115.002796allogeneic transplantationcardioprotective effectcardiosphere‐derived cells |
| spellingShingle | 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 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: Cardiovascular and Cerebrovascular Disease allogeneic transplantation cardioprotective effect cardiosphere‐derived cells |
| title | Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction |
| title_full | Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction |
| title_fullStr | Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction |
| title_full_unstemmed | Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction |
| title_short | Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction |
| title_sort | durable benefits of cellular postconditioning long term effects of allogeneic cardiosphere derived cells infused after reperfusion in pigs with acute myocardial infarction |
| topic | allogeneic transplantation cardioprotective effect cardiosphere‐derived cells |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.115.002796 |
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