title: The impact of patient co-morbidities on the regenerative capacity of cardiac explant-derived stem cells.
abstract: BACKGROUND
  Although patient-sourced cardiac stem cells repair damaged myocardium, the extent to which medical co-morbidities influence cardiac-derived cell products is uncertain. Therefore, we investigated the influence of atherosclerotic risk factors on the regenerative performance of human cardiac explant-derived cells (EDCs).
  
  
  METHODS
  In this study, the Long Term Stratification for survivors of acute coronary syndromes model was used to quantify the burden of cardiovascular risk factors within a group of patients with established atherosclerosis. EDCs were cultured from human atrial appendages and injected into immunodeficient mice 7 days post-left coronary ligation. Cytokine arrays and enzyme linked immunoassays were used to determine the release of cytokines by EDCs in vitro, and echocardiography was used to determine regenerative capabilities in vivo.
  
  
  RESULTS
  EDCs sourced from patients with more cardiovascular risk factors demonstrated a negative correlation with production of pro-healing cytokines (such as stromal cell derived factor 1α) and exosomes which had negative effects on the promotion of angiogenesis and chemotaxis. Reductions in exosomes and pro-healing cytokines with accumulating medical co-morbidities were associated with increases in production of the pro-inflammatory cytokine interleukin-6 (IL-6) by EDCs. Increased patient co-morbidities were also correlated with significant attenuation in improvements of left ventricular ejection fraction.
  
  
  CONCLUSIONS
  The regenerative performance of the earliest precursor cell population cultured from human explant tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 is markedly increased. Predictors of cardiac events demonstrated a lower capacity to support angiogenesis and repair injured myocardium in a mouse model of myocardial infarction.
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Mayfield
authors.affiliation: Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, K1H8L6, Canada.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Fitzpatrick
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Latham
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Everad L
authors.initials: EL
authors.lastname: Tilokee
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Villanueva
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Seth
authors.initials: S
authors.lastname: Mount
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Bu-Khanh
authors.initials: BK
authors.lastname: Lam
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, K1H8L6, Canada.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada. ddavis@ottawaheart.ca.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Davis
mesh_terms: D054058:Acute Coronary Syndrome / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000378:metabolism; D002633:Chemotaxis; D015897:Comorbidity; D023921:Coronary Stenosis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D055354:Exosomes / Q000637:transplantation; D015870:Gene Expression; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic; D061251:Primary Cell Culture; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013318:Stroke Volume; D016277:Ventricular Function, Left
chemical_list: D054377:Chemokine CXCL12; D015850:Interleukin-6
keywords: Cell transplantation; Cytokine; Heart failure; Stem cell