Abstract
BACKGROUND: Intracoronary (IC) infusion of cardiosphere-derived stem cells (CDCs) under stop-flow conditions has proven efficacious in producing myocardial regeneration in preclinical and clinical studies. However, the minimally-effective dose is not known, nor is it clear whether benefit is straightforwardly dependent on CDC dose. OBJECTIVE: To determine the dose-efficacy relationship of allogeneic CDCs in a large-animal chronic myocardial infarction (MI) model. METHODS: Escalating doses of allogeneic CDCs (3.125M, 6.25M, 12.5M, 25M; or vehicle as a control) were infused into the left anterior descending coronary artery using a nonocclusive guiding catheter in an anterior chronic MI minipig model. Magnetic resonance imaging (MRI) was used to assess structural and functional endpoints. RESULTS: CDCs were infused in a total of 25 animals under continuous flow at a rate of 1.25M CDCs/min. An additional 5 control animals underwent continuous flow of vehicle over 10 min. No animals experienced adverse events during or after the infusions. One month post therapy, ejection fraction (EF) was preserved at doses of 6.25M, 12.5M and 25M, but not with 3.125 M allo-CDCs or control (ΔEF = -6.7±0.9% in the placebo, -5.1±1.8% in 3.125M, -1.4±0.6% in the 6.25M, -2±1.4% in the 12.5M and -2.3±1.2% in the 25M group; p=0.04 by one way ANOVA for treatment effect). All doses of CDCs (except 3.125M) led to equivalent scar mass reductions, as assessed by MRI with Gd enhancement (p=0.0037 treated vs placebo, one-way ANOVA). Provocative electrophysiology testing at the end of the study revealed no enhanced arrythmogenic potential after cell therapy. CONCLUSIONS: Allogeneic CDCs can be safely administered with a non-occlusive method, over a wide dosage range. All doses >3.125M lead to enhanced preservation of left ventricular function and tissue remodeling, but to similar degrees. Our data reveal that CDCs work by a “threshold” effect that does not obey classical drug-receptor kinetics. This finding is consistent with the extraordinary ability of seemingly-homeopathic doses to exert large, lasting benefits.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
