title: Noninvasive imaging of myocyte apoptosis following application of a stem cell-engineered delivery platform to acutely infarcted myocardium.
abstract: The cardioprotective effects of mesenchymal stem cells (MSCs) include reducing myocyte apoptosis, and this effect can be enhanced by preconditioning and encapsulation in a fibrin scaffold. This study aimed to test the hypothesis that apoptosis imaging can detect the cardioprotective effects of a conditioned MSC patch grafted in a rat model of acute myocardial infarction.
  
  
  METHODS
  Cell culture experiments simulating engraftment of fibrin patches onto beating rat ventricular myocytes exposed to hypoxia showed an effect of conditioned cells to reduce apoptosis. Twenty-three nude rats underwent successful left anterior descending coronary artery occlusion and were divided into 3 groups: transforming growth factor β1-conditioned human MSC-laden patches (CP), infarct alone without patch (no patch [NP]), and patch alone (patch only [PO]). Twenty-four hours after myocardial infarction, all rats were injected with (99m)Tc-hydrazinonicotinamide ((99m)Tc-HYNIC) annexin V and (201)Tl and underwent dual-isotope SPECT/CT imaging. Six rats were sacrificed for histology and counting. The remaining rats (n = 17; 1 rat was eliminated) were injected and imaged on day 7; of those, 3 rats were sacrificed for histology and counting, and the remaining 13 rats survived to day 21, when they were sacrificed for histology. Numbers of rats imaged on day 7 in the 3 groups were 7 in the CP group, 5 in the NP, and 5 in the PO. Perfused myocardium, infarct size, and (99m)Tc-HYNIC annexin V uptake were quantified from the scans from days 1 and 7. (99m)Tc-HYNIC annexin V uptake was correlated with quantitative caspase staining, and infarct size as percentage fibrosis was quantified at day 21.
  
  
  RESULTS
  (99m)Tc-HYNIC annexin V uptake as percentage injected dose (×10(-4)) decreased between days 1 and 7 by 1.04 ± 0.28 in the CP group, 0.44 ± 0.17 in the NP group, and 0.34 ± 0.27 in the PO group (P = 0.003 for NP vs. CP, P = 0.005 for PO vs. CP, and P = 0.5 for NP vs. CP). The changes in defect size as percentage myocardium between days 1 and 7 were -8.83 ± 4.40 in the CP group, +1.00 ± 2.24 in the NP group, and -0.50 ± 4.20 in the PO group (P = 0.003 for NP vs. CP, P = 0.005 for PO vs. CP, and P = 0.50 for NP vs. PO). (99m)Tc-HYNIC annexin V uptake as percentage left ventricle by scanning correlated with caspase staining (r = 0.931, P = 0.002).
  
  
  CONCLUSIONS
  Transforming growth factor β1-conditioned human MSC-laden patches reduce myocyte apoptosis in the setting of acute infarction, and this effect can be detected by in vivo imaging with (99m)Tc-HYNIC annexin V.
authors.affiliation: Department of Biomedical Engineering, Columbia University Medical Center, New York, New York, USA.
authors.forename: Amandine F G
authors.initials: AF
authors.lastname: Godier-Furnémont
authors.forename: Yared
authors.initials: Y
authors.lastname: Tekabe
authors.forename: Maria
authors.initials: M
authors.lastname: Kollaros
authors.forename: George
authors.initials: G
authors.lastname: Eng
authors.forename: Alfredo
authors.initials: A
authors.lastname: Morales
authors.forename: Gordana
authors.initials: G
authors.lastname: Vunjak-Novakovic
authors.forename: Lynne L
authors.initials: LL
authors.lastname: Johnson
mesh_terms: D000208:Acute Disease; D000818:Animals; D017304:Annexin A5; D017209:Apoptosis; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D064847:Multimodal Imaging; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000473:pathology* / Q000628:therapy; D032383:Myocytes, Cardiac / Q000473:pathology*; D009929:Organ Size; D015609:Organotechnetium Compounds; D049268:Positron-Emission Tomography; D051381:Rats; D011923:Rats, Nude; D023822:Tissue Engineering / Q000379:methods*; D014057:Tomography, X-Ray Computed
chemical_list: D017304:Annexin A5; D015609:Organotechnetium Compounds; C417036:technetium Tc 99m annexin V
keywords: apoptosis; engineered cardiac tissue; myocardial infarction; radionuclides; stem cells