title: Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution.
abstract: OBJECTIVE
  To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery.
  
  
  BACKGROUND
  Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium.
  
  
  METHODS
  In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery.
  
  
  RESULTS
  IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route.
  
  
  CONCLUSIONS
  Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise.
authors.affiliation: Krannert Institute of Cardiology, Indianapolis; Indiana Center for Vascular Biology and Medicine, Indianapolis; Indiana University School of Medicine, Indianapolis, Indianapolis; Korea University Anam Hospital, Seoul, Korea.
authors.forename: Soon Jun
authors.initials: SJ
authors.lastname: Hong
authors.forename: Dongming
authors.initials: D
authors.lastname: Hou
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Brinton
authors.forename: Brian
authors.initials: B
authors.lastname: Johnstone
authors.forename: Dongni
authors.initials: D
authors.lastname: Feng
authors.forename: Pamela
authors.initials: P
authors.lastname: Rogers
authors.forename: William F
authors.initials: WF
authors.lastname: Fearon
authors.forename: Paul
authors.initials: P
authors.lastname: Yock
authors.forename: Keith L
authors.initials: KL
authors.lastname: March
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D058948:Cell Tracking / Q000379:methods; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000503:physiopathology*; D004195:Disease Models, Animal; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008168:Lung / Q000098:blood supply* / Q000000981:diagnostic imaging; D008833:Microcirculation; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000473:pathology*; D011652:Pulmonary Circulation; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013552:Swine; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D014655:Vascular Resistance