Christian P Brizard1, Jeffrey Y J Looi2, Joseph J Smolich3, Stephen B Horton4, Julie Angerosa5, Ngaire J Elwood6, Salvatore Pepe7. 1. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia; Department of Cardiac Surgery, The Royal Children's Hospital, Melbourne, Victoria, Australia. 2. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia; Cord Blood Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. 3. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia. 4. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Cardiac Surgery, The Royal Children's Hospital, Melbourne, Victoria, Australia. 5. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. 6. Cord Blood Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia. 7. Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: salvatore.pepe@mcri.edu.au.
Abstract
BACKGROUND: One potential approach for advancing univentricular heart surgical palliation outcomes is by stem cell therapy to augment right ventricular function and muscle mass. Whether the stem cell-inclusive cord blood mononuclear cells (CBMNCs) are safe to perfuse into the coronary vasculature during neonatal cardiopulmonary bypass (CPB) is unknown. We evaluated the acute safety, functional effects, and fate of human CBMNCs in a novel model of coronary vasculature delivery in a lamb model of infant CPB. METHODS: Neonatal lambs were randomized in blinded fashion to receive control (n = 5) or human CD45(+) CBMNCs (8 × 10(6) cells/kg body weight, n = 7) treatments during CPB. Aortic cross-clamp time was 40 minutes, with maintenance blood cardioplegia delivered every 10 minutes. Pressure-volume indices were used to measure left ventricular function before CPB and 60 minutes after CPB. CBMNCs were assessed by flow cytometry and immunohistochemistry. RESULTS: CBMNC-treated lambs were hemodynamically stable after CPB, with a decline in left ventricular pressure-volume indices similar to controls. The coronary vasculature was patent on microscopy, without evidence of cell aggregates or clots. Human CD45(+) cells were distributed in high abundance within all cardiac regions, predominantly the right atrium and ventricles, and trafficked beyond endothelial cell layers and between myocytes. CD45(+) cells localized at low incidence in the spleen, liver, lungs, and kidneys, but rarely remained in the circulation (<0.1% of infused cells). CONCLUSIONS: Coronary delivery of human CBMNCs during blood-cardioplegic arrest in a lamb model of CPB results in highly abundant myocardial distribution of cells without acute adverse effects on vascular patency and post-CPB cardiac function.
BACKGROUND: One potential approach for advancing univentricular heart surgical palliation outcomes is by stem cell therapy to augment right ventricular function and muscle mass. Whether the stem cell-inclusive cord blood mononuclear cells (CBMNCs) are safe to perfuse into the coronary vasculature during neonatal cardiopulmonary bypass (CPB) is unknown. We evaluated the acute safety, functional effects, and fate of human CBMNCs in a novel model of coronary vasculature delivery in a lamb model of infant CPB. METHODS: Neonatal lambs were randomized in blinded fashion to receive control (n = 5) or humanCD45(+) CBMNCs (8 × 10(6) cells/kg body weight, n = 7) treatments during CPB. Aortic cross-clamp time was 40 minutes, with maintenance blood cardioplegia delivered every 10 minutes. Pressure-volume indices were used to measure left ventricular function before CPB and 60 minutes after CPB. CBMNCs were assessed by flow cytometry and immunohistochemistry. RESULTS: CBMNC-treated lambs were hemodynamically stable after CPB, with a decline in left ventricular pressure-volume indices similar to controls. The coronary vasculature was patent on microscopy, without evidence of cell aggregates or clots. HumanCD45(+) cells were distributed in high abundance within all cardiac regions, predominantly the right atrium and ventricles, and trafficked beyond endothelial cell layers and between myocytes. CD45(+) cells localized at low incidence in the spleen, liver, lungs, and kidneys, but rarely remained in the circulation (<0.1% of infused cells). CONCLUSIONS: Coronary delivery of human CBMNCs during blood-cardioplegic arrest in a lamb model of CPB results in highly abundant myocardial distribution of cells without acute adverse effects on vascular patency and post-CPB cardiac function.
Authors: Christopher R Nitkin; Johnson Rajasingh; Courtney Pisano; Gail E Besner; Bernard Thébaud; Venkatesh Sampath Journal: Pediatr Res Date: 2019-05-14 Impact factor: 3.756