Global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium.
BACKGROUND
Cardiosphere-derived cells (CDCs) improve ventricular function and reduce fibrotic volume when administered via an infarct-related artery using the "stop-flow" technique. Unfortunately, myocyte loss and dysfunction occur globally in many patients with ischemic and non-ischemic cardiomyopathy, necessitating an approach to distribute CDCs throughout the entire heart. We therefore determined whether global intracoronary infusion of CDCs under continuous flow improves contractile function and stimulates new myocyte formation.


RESULTS
Swine with hibernating myocardium from a chronic LAD occlusion were studied 3-months after instrumentation (n = 25). CDCs isolated from myocardial biopsies were infused into each major coronary artery (∼ 33 × 10(6) icCDCs). Global icCDC infusion was safe and while ∼ 3% of injected CDCs were retained, they did not affect ventricular function or myocyte proliferation in normal animals. In contrast, four-weeks after icCDCs were administered to animals with hibernating myocardium, %LADWT increased from 23 ± 6 to 51 ± 5% (p<0.01). In diseased hearts, myocyte proliferation (phospho-histone-H3) increased in hibernating and remote regions with a concomitant increase in myocyte nuclear density. These effects were accompanied by reductions in myocyte diameter consistent with new myocyte formation. Only rare myocytes arose from sex-mismatched donor CDCs.


CONCLUSIONS
Global icCDC infusion under continuous flow is feasible and improves contractile function, regresses myocyte cellular hypertrophy and increases myocyte proliferation in diseased but not normal hearts. New myocytes arising via differentiation of injected cells are rare, implicating stimulation of endogenous myocyte regeneration as the primary mechanism of repair.
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Gen
G
Suzuki
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Brian R
BR
Weil
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Merced M
MM
Leiker
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Amanda E
AE
Ribbeck
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Rebeccah F
RF
Young
Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
Thomas R
TR
Cimato
Division of Cardiovascular Medicine, Veterans Affairs Western New York Health Care System, Buffalo, New York, United States of America; Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Buffalo, New York, United States of America; Department of Physiology & Biophysics, University at Buffalo, Buffalo, New York, United States of America; Department of Biomedical Engineering, University at Buffalo, Buffalo, New York, United States of America; The Clinical and Translational Research Center, University at Buffalo, Buffalo, New York, United States of America.
John M
JM
Canty
D000818:Animals; D009202:Cardiomyopathies / Q000473:pathology*; D049109:Cell Proliferation; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000473:pathology*; D005434:Flow Cytometry; D006321:Heart / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007261:Infusions, Intra-Arterial; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000637:transplantation*; D012038:Regeneration / Q000502:physiology*; D013552:Swine; D014184:Transplantation, Homologous; D016276:Ventricular Function / Q000502:physiology*