title: Permanent coronary artery occlusion: cardiovascular MR imaging is platform for percutaneous transendocardial delivery and assessment of gene therapy in canine model.
abstract: OBJECTIVE
  To provide evidence that vascular endothelial growth factor (VEGF) genes delivered transendocardially with magnetic resonance (MR) imaging guidance may neovascularize or improve vascular recruitment in occlusive infarction.
  
  
  METHODS
  All experimental procedures received approval from the institutional committee on animal research. Dogs with permanent coronary artery occlusion were imaged twice (3 days after occlusion for assessment of acute infarction; a mean of 50 days after occlusion +/- 3 [standard error of the mean] for assessment of chronic infarction). A mixture of plasmid VEGF and plasmid LacZ (n = 6, treated animals) or plasmid LacZ and sprodiamide (n = 6, placebo control animals) was delivered to four sites. MR fluoroscopy was used to target and monitor delivery of genes. The effectiveness of this delivery approach was determined by using MR imaging methods to assess perfusion, left ventricular (LV) function, myocardial viability, and infarct resorption. Histologic evaluation of neovascularization was then performed.
  
  
  RESULTS
  MR fluoroscopic guidance of injectates was successful in both groups. Treated animals with chronic, but not those with acute, infarction showed the following differences compared with control animals: (a) steeper mean maximum upslope perfusion (200 sec(-1) +/- 32 vs 117 sec(-1) +/- 15, P = .02), (b) higher peak signal intensity (1667 arbitrary units +/- 100 vs 1132 arbitrary units +/- 80, P = .002), (c) increased ejection fraction (from 27.9% +/- 1.2 to 35.3% +/- 1.6, P = .001), (d) smaller infarction size (as a percentage of LV mass) at MR imaging (8.5% +/- 0.9 vs 11.3% +/- 0.9, P = .048) and triphenyltetrazolium chloride staining (9.4% +/- 1.5 vs 12.7% +/- 0.4, P = .05), and (e) higher vascular density (as number of vessels per square millimeter) at the border (430 +/- 117 vs 286 +/- 19, P = .0001) and core (307 +/- 112 vs 108 +/- 17, P = .0001).
  
  
  CONCLUSIONS
  The validity of plasmid VEGF gene delivered with MR fluoroscopic guidance into occlusive infarction was confirmed by neovascularization associated with improved perfusion, LV function, and infarct resorption.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94134-0628, USA. Maythem.Saeed@radiology.UCSF.edu
authors.forename: Maythem
authors.initials: M
authors.lastname: Saeed
authors.forename: Alastair
authors.initials: A
authors.lastname: Martin
authors.forename: Alexis
authors.initials: A
authors.lastname: Jacquier
authors.forename: Matthew
authors.initials: M
authors.lastname: Bucknor
authors.forename: David
authors.initials: D
authors.lastname: Saloner
authors.forename: Loi
authors.initials: L
authors.lastname: Do
authors.forename: Philip
authors.initials: P
authors.lastname: Ursell
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Yuet W
authors.initials: YW
authors.lastname: Kan
authors.forename: Charles B
authors.initials: CB
authors.lastname: Higgins
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage; D054059:Coronary Occlusion / Q000188:drug therapy*; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D053783:Magnetic Resonance Imaging, Interventional / Q000379:methods*; D008536:Meglumine / Q000008:administration & dosage; D009942:Organometallic Compounds / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008536:Meglumine; C072417:gadoterate meglumine
references.citation: Circulation. 2002 Apr 30;105(17):2012-8
references.pmid: 11980678
references.citation: N Engl J Med. 2000 Mar 2;342(9):626-33
references.pmid: 10699162
references.citation: Eur Radiol. 2005 May;15(5):851-63
references.pmid: 15856250
references.citation: Circulation. 1991 Nov;84(5):2071-8
references.pmid: 1657448
references.citation: Circ Res. 2006 Apr 14;98(7):954-61
references.pmid: 16543500
references.citation: Circulation. 2003 May 13;107(18):2290-3
references.pmid: 12732608
references.citation: Circulation. 2002 Aug 27;106(9):1140-6
references.pmid: 12196342
references.citation: J Mol Cell Cardiol. 2007 May;42(5):954-61
references.pmid: 17484913
references.citation: Am Heart J. 1996 Nov;132(5):921-32
references.pmid: 8892762
references.citation: Heart. 2007 Jul;93(7):842-7
references.pmid: 17344328
references.citation: Eur Radiol. 2006 Apr;16(4):827-36
references.pmid: 16362420
references.citation: Gene Ther. 2006 Aug;13(15):1133-42
references.pmid: 16572192
references.citation: J Am Coll Cardiol. 2004 Jun 2;43(11):2124-31
references.pmid: 15172424
references.citation: Circulation. 2005 Sep 6;112(10):1451-61
references.pmid: 16129797
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1721-4
references.pmid: 12767654
references.citation: Circulation. 2003 Dec 9;108(23):2899-904
references.pmid: 14656911
references.citation: Nat Med. 2005 Nov;11(11):1197-204
references.pmid: 16244652
references.citation: Magn Reson Med. 2004 Jun;51(6):1163-72
references.pmid: 15170836
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13801-6
references.pmid: 11095751
references.citation: Phys Med Biol. 2006 Jul 21;51(14):R505-40
references.pmid: 16825730
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71
references.pmid: 15951423
references.citation: Int J Cardiovasc Intervent. 2005;7(4):165-70
references.pmid: 16373261
references.citation: Eur Heart J. 2007 Mar;28(5):522-4
references.pmid: 17314109
references.citation: Catheter Cardiovasc Interv. 2001 Feb;52(2):260-6
references.pmid: 11170342
references.citation: Radiology. 2006 Aug;240(2):419-26
references.pmid: 16801371
references.citation: Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1393-405
references.pmid: 16387794
references.citation: Curr Interv Cardiol Rep. 2001 Aug;3(3):192-197
references.pmid: 11485688
references.citation: J Anat. 2002 Jun;200(6):581-97
references.pmid: 12162726
references.citation: Catheter Cardiovasc Interv. 2006 Sep;68(3):372-8
references.pmid: 16892433
references.citation: Radiology. 2007 Oct;245(1):196-205
references.pmid: 17885189
references.citation: Circulation. 2003 Aug 26;108(8):1009-14
references.pmid: 12912822
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16280-5
references.pmid: 15534198
references.citation: Eur Heart J. 2005 Mar;26(6):549-57
references.pmid: 15713695
references.citation: Radiology. 2007 May;243(2):451-60
references.pmid: 17384240
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9480-5
references.pmid: 12084814
references.citation: J Card Fail. 2002 Dec;8(6 Suppl):S472-5
references.pmid: 12555160
references.citation: Radiology. 2004 Jun;231(3):689-96
references.pmid: 15163809
references.citation: Radiology. 2001 Jan;218(1):215-23
references.pmid: 11152805
references.citation: Circulation. 2007 Apr 10;115(14):1866-75
references.pmid: 17389266
references.citation: J Am Coll Cardiol. 2004 Jun 16;43(12):2253-9
references.pmid: 15193689
references.citation: Nat Clin Pract Cardiovasc Med. 2007 Feb;4 Suppl 1:S1-8
references.pmid: 17230204
references.citation: Am Heart J. 1990 Jun;119(6):1367-73
references.pmid: 2141222
references.citation: Radiology. 2007 Oct;245(1):95-102
references.pmid: 17885184
references.citation: Genes Dev. 2005 Jul 1;19(13):1624-34
references.pmid: 15998812
references.citation: J Am Coll Cardiol. 2006 Nov 21;48(10):1961-8
references.pmid: 17112985