Abstract
Single-vessel, intracoronary infusion of stem cells under stop-flow conditions has proven safe but achieves only limited myocardial coverage. Continuous flow intracoronary delivery to one or more coronary vessels may achieve broader coverage for treating cardiomyopathy, but has not been investigated. Using nonocclusive coronary guiding catheters, we infused allogeneic cardiosphere-derived cells (CDCs) either in a single vessel or sequentially in all three coronary arteries in porcine ischemic cardiomyopathy and used magnetic resonance imaging (MRI) to assess structural and physiological outcomes. Vehicle-infused animals served as controls. Single-vessel stop-flow and continuous-flow intracoronary infusion revealed equivalent effects on scar size and function. Sequential infusion into each of the three major coronary vessels under stop-flow or continuous-flow conditions revealed equal efficacy, but less elevation of necrotic biomarkers with continuous-flow delivery. In addition, multi-vessel delivery resulted in enhanced global and regional tissue function compared to a triple-vessel placebo-treated group. The functional benefits after global cell infusion were accompanied histologically by minimal inflammatory cellular infiltration, attenuated regional fibrosis and enhanced vessel density in the heart. Sequential multi-vessel non-occlusive delivery of CDCs is safe and provides enhanced preservation of left ventricular function and structure. The current findings provide preclinical validation of the delivery method currently undergoing clinical testing in the Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial of CDCs in heart failure patients.
Highlights
The field of cell therapy has been plagued by uncertainties regarding delivery methods[1], a factor likely contributing to inconsistent results in the clinic [2,3]
In cell therapy for myocardial infarction (MI), the standard stop-flow intracoronary (IC) approach uses an over-the-wire angioplasty catheter, which is repeatedly inflated in the infarct-related artery; cells are infused during inflations [4]
Three animals were used for peripheral blood mononuclear cells (PBMC) injections and three animals to evaluate three-vessel cardiosphere-derived cells (CDCs) engraftment
Summary
The field of cell therapy has been plagued by uncertainties regarding delivery methods[1], a factor likely contributing to inconsistent results in the clinic [2,3]. Systematic preclinical optimization of delivery in large-animal models is rarely performed, we posit that such studies are vital as they may decrease the number of failures in translation [7,8,9]. Based on this premise, we questioned prevailing assumptions regarding the need for stop flow, and we tested multivessel delivery in an effort to achieve safe, effective delivery to the pumping chambers of the heart. We tested the safety and efficacy of sequential multi-vessel non-occlusive IC delivery of CDCs, using magnetic resonance imaging (MRI) and histology to assess cardiac structure and function. The use of MRI establishes direct links to clinically-tractable in vivo endpoints, while the use of histology provides validation for the MRI findings as well as useful information regarding the effects of cell therapy on angiogenesis and fibrosis
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