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

PLoS One. 2016 Jan 19;11(1):e0144523. doi: 10.1371/journal.pone.0144523. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathy, Hypertrophic / diagnosis
  • Cardiomyopathy, Hypertrophic / etiology
  • Cardiomyopathy, Hypertrophic / pathology
  • Cardiomyopathy, Hypertrophic / physiopathology
  • Cell- and Tissue-Based Therapy
  • Disease Models, Animal
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Myoblasts, Cardiac / cytology*
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / mortality
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy
  • Myocardial Ischemia / diagnosis
  • Myocardial Ischemia / mortality
  • Myocardial Ischemia / pathology*
  • Myocardial Ischemia / physiopathology
  • Myocardial Ischemia / therapy*
  • Phenotype
  • Stem Cell Transplantation*
  • Stem Cells / cytology*
  • Stroke Volume
  • Swine
  • Ventricular Remodeling

Grant support

This work was supported by the Cedars-Sinai Board of Governors Heart Stem Cell Center. The Cedars-Sinai Board of Governors Heart Stem Cell Center provided support in the form of salaries for authors ET, HK, JD, JV, RM, RM, SK and EM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. RS, LM and MK are employed by Capricor Inc but did not participate in the funding of this study nor did they play a role in the study design, data collection, decision to publish, or preparation of the manuscript.