title: Markers of progenitor cell recruitment and differentiation rise early during ischemia and continue during resuscitation in a porcine acute ischemia model.
abstract: Clinical administration of bone marrow-derived stem cells in the setting of acute myocardial infarction (AMI) leads to improved left ventricular ejection fraction. Thymosin beta-4 (TB4) and vascular endothelial growth factor (VEGF) are linked to adult epicardial progenitor cell mobilization and neovascularization and is cardioprotective after myocardial ischemia. This study investigated the time course of TB4 and VEGF during AMI, cardiac arrest, and resuscitation. Fifteen anesthetized and instrumented domestic swine underwent balloon occlusion of the proximal left anterior descending coronary artery. During occlusion, venous blood samples were collected from the right atrium at 5-min intervals until 15 min after the onset of cardiopulmonary resuscitation (CPR). Plasma levels of TB4, VEGF, and matrix metalloproteinase-9 (MMP-9, selected as a marker for remodeling and repair) were measured by ELISA. Generalized linear mixed models were employed to model the time-dependent change in plasma concentration. All variables were natural log transformed, except TB4 values, to normalize distributions. Fifteen animals successfully underwent balloon occlusion of the left anterior descending coronary artery and samples were collected from these subjects. The average onset of spontaneous ventricular fibrillation was 28 min. TB4, VEGF, and MMP-9 demonstrated a statistically significant, time-dependent increase in concentration during ischemia. Following arrest and throughout the first 15 min of resuscitation, MMP-9 had an unchanged rate of rise when compared with the prearrest, ischemic period, with VEGF showing a deceleration in its time-dependent concentration trajectory and TB4 demonstrating an acceleration. Endogenous TB4 and VEGF increase shortly after the onset of AMI and increase through cardiac arrest and resuscitation in parallel to remodeling proteases. These markers continue to rise during successful resuscitation and may represent an endogenous mechanism to recruit undifferentiated stem cells to areas of myocardial injury.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. ashah5@uchicago.edu
authors.forename: Atman P
authors.initials: AP
authors.lastname: Shah
authors.forename: Scott T
authors.initials: ST
authors.lastname: Youngquist
authors.forename: Christian D
authors.initials: CD
authors.lastname: McClung
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Tzvetkova
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Hanif
authors.forename: John P
authors.initials: JP
authors.lastname: Rosborough
authors.forename: James T
authors.initials: JT
authors.lastname: Niemann
mesh_terms: D000818:Animals; D021721:Balloon Occlusion; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D004195:Disease Models, Animal; D006323:Heart Arrest; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D044968:Regenerative Medicine; D012151:Resuscitation; D033581:Stem Cell Transplantation; D013552:Swine; D013947:Thymosin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling; D000099201:Thymosin beta(4)
chemical_list: D015415:Biomarkers; D020780:Matrix Metalloproteinase 9; D013947:Thymosin; D042461:Vascular Endothelial Growth Factor A; D000099201:Thymosin beta(4)