title: Widespread Myocardial Delivery of Heart-Derived Stem Cells by Nonocclusive Triple-Vessel Intracoronary Infusion in Porcine Ischemic Cardiomyopathy: Superior Attenuation of Adverse Remodeling Documented by Magnetic Resonance Imaging and Histology.
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.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Dawkins
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Romain
authors.initials: R
authors.lastname: Gallet
authors.affiliation: Capricor Inc., Los Angeles, CA, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kreke
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.|Capricor Inc., Los Angeles, CA, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Smith
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Middleton
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Jackelyn
authors.initials: J
authors.lastname: Valle
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.|Capricor Inc., Los Angeles, CA, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Saibal
authors.initials: S
authors.lastname: Kar
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Makkar
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America.|Capricor Inc., Los Angeles, CA, United States of America.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D032386:Myoblasts, Cardiac / Q000166:cytology*; D009203:Myocardial Infarction / Q000175:diagnosis / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D010641:Phenotype; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013318:Stroke Volume; D013552:Swine; D020257:Ventricular Remodeling