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Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.

ABSTRACT: 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.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-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.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.

SUBMITTER: Kanazawa H

PROVIDER: S-EPMC4802479 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.

Kanazawa Hideaki H Tseliou Eleni E Dawkins James F JF De Couto Geoffrey G Gallet Romain R Malliaras Konstantinos K Yee Kristine K Kreke Michelle M Valle Ileana I Smith Rachel R RR Middleton Ryan C RC Ho Chak-Sum CS Dharmakumar Rohan R Li Debiao D Makkar Raj R RR Fukuda Keiichi K Marbán Linda L Marbán Eduardo E

Journal of the American Heart Association 20160208 2

<h4>Background</h4>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.<h4>Methods and results</h4>Minipigs underwent 1.5-hour mid-left anterior descending balloon occlusion followed by reperfusi ...[more]

PMID: 26857066

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Project description:Intracoronary cardiosphere-derived cells (icCDCs) infused into the infarct-related artery reduce scar volume but do not improve left ventricular (LV) ejection fraction (LVEF). We tested the hypothesis that this reflects the inability of regional delivery to prevent myocyte death or promote myocyte proliferation in viable myocardium remote from the infarct. Swine (n = 23) pretreated with oral cyclosporine (200 mg/day) underwent a 1-h left anterior descending coronary artery (LAD) occlusion, which reduced LVEF from 61.6?±?1.0 to 45.3?±?1.5% 30 min after reperfusion. At that time, animals received global infusion of allogeneic icCDCs (n = 8), regional infusion of icCDCs restricted to the LAD using the stop-flow technique (n = 8), or vehicle (n = 7). After 1 mo, global icCDCs increased LVEF from 44.8?±?1.9 to 60.8?±?3.8% (P < 0.05) with no significant change after LAD stop-flow icCDCs (44.8?±?3.6 to 50.9?±?3.1%) or vehicle (46.5?±?2.5 to 47.7?±?2.6%). In contrast, global icCDCs did not alter infarct volume (%LV mass) assessed at 2 days (11.2?±?2.3 vs. 12.6?±?2.3%), whereas it was reduced after LAD stop-flow icCDCs (7.1?±?1.1%, P < 0.05). Histopathological analysis of remote myocardium after global icCDCs demonstrated a significant increase in myocyte proliferation (147?±?32 vs. 14?±?10 nuclei/106 myocytes, P < 0.05) and a reduction in myocyte apoptosis (15?±?9 vs. 46?±?10 nuclei/106 myocytes, P < 0.05) that increased myocyte nuclear density (1,264?±?39 vs. 1,157?±?33 nuclei/mm2, P < 0.05) and decreased myocyte diameter (13.2?±?0.2 vs. 14.5?±?0.3 ?m, P < 0.05) compared with vehicle-treated controls. In contrast, remote zone changes after regional LAD icCDCs were no different from vehicle. These data indicate that changes in global LVEF after icCDCs are dependent upon preventing myocyte loss and hypertrophy in myocardium remote from the infarct. These arise from stimulating myocyte proliferation and reducing myocyte apoptosis indicating the importance of directing cell therapy to viable remote regions.NEW & NOTEWORTHY Administration of allogeneic cardiosphere-derived cells to the entire heart via global intracoronary infusion shortly after myocardial infarction favorably influenced left ventricular ejection fraction by preventing myocyte death and promoting myocyte proliferation in remote, noninfarcted myocardium in swine. In contrast, regional intracoronary cell infusion did not significantly affect remote zone myocyte remodeling. Global cell administration targeting viable myocardium remote from the infarct may be an effective approach to prevent adverse ventricular remodeling after myocardial infarction.

Dataset Information

Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.

Publications

Durable Benefits of Cellular Postconditioning: Long-Term Effects of Allogeneic Cardiosphere-Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction.

Similar Datasets

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