Journal of Nuclear Cardiology

, Volume 11, Issue 4, pp 491–505

Molecular imaging of cardiovascular gene products

  • Joseph C. Wu
  • Jeffrey R. Tseng
  • Sanjiv S. Gambhir
From bench to imaging


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid [letter]. Nature 1953;171:737–88.PubMedCrossRefGoogle Scholar
  2. 2.
    Phelps ME. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A 2000;97:9226–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Haider N, Iyer RR, Narula J. Topics in molecular biology. Techniques and methods. J Nucl Cardiol 1998;5:343–54.PubMedCrossRefGoogle Scholar
  4. 4.
    Iyer RR, Schelbert H, Haider N, et al. Molecular biology for the nuclear cardiologist: terminology, concepts, and processes. J Nucl Cardiol 1998;5:184–94.PubMedCrossRefGoogle Scholar
  5. 5.
    Narula N, Haider N, Narula J. Cell biology for the nuclear cardiologist. J Nucl Cardiol 1998;5:426–37.PubMedCrossRefGoogle Scholar
  6. 6.
    Lee KH, Hajjar RJ, Matsui T, et al. Cardiac signal transduction. J Nucl Cardiol 2000;7:63–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Yla-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 2003;9:694–701.PubMedCrossRefGoogle Scholar
  8. 8.
    Zuckerbraun BS, Tzeng E. Vascular gene therapy: a reality of the 21st century. Arch Surg 2002;137:854–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Lake Tahoe invitation meeting 2002. J Nucl Cardiol 2003;10:223- 57.Google Scholar
  10. 10.
    Yla-Herttuala S, Martin JF. Cardiovascular gene therapy. Lancet 2000;355:213–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Takeshita S, Pu LQ, Stein LA, et al.. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation 1994;90:II228–34.PubMedGoogle Scholar
  12. 12.
    Brogi E, Wu T, Namiki A, et al.. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 1994;90:649–52.PubMedGoogle Scholar
  13. 13.
    Shyu KG, Wang MT, Wang BW, et al.. Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 2002;54:576–83.PubMedCrossRefGoogle Scholar
  14. 14.
    Steg PG, Tahlil O, Aubailly N, et al.. Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy. Circulation 1997;96:408–11.PubMedGoogle Scholar
  15. 15.
    Miyamoto MI, del Monte F, Schmidt U, et al.. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aorticbanded rats in transition to heart failure. Proc Natl Acad Sci U S A 2000;97:793–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Kozarsky KF, Donahee MH, Glick JM, et al.. Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol 2000;20:721–7.PubMedGoogle Scholar
  17. 17.
    Matsui T, Li L, del Monte F, et al.. Adenoviral gene transfer of activated phosphatidylinositol 3’kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 1999;100:2373–9.PubMedGoogle Scholar
  18. 18.
    National Institutes of Health Office of Biotechnology Advances. Clinical trials in human gene transfer: query of clinical trials. Available from: URL: form.asp. Accessed June 14, 2004.Google Scholar
  19. 19.
    Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999;77:527–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Rosengart TK, Lee LY, Patel SR, et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 1999;100:468–74.PubMedGoogle Scholar
  21. 21.
    Symes JF, Losordo DW, Vale PR, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 1999;68:830–6; discussion 836-7.PubMedCrossRefGoogle Scholar
  22. 22.
    Vale PR, Losordo DW, Milliken CE, et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000;102:965–74.PubMedGoogle Scholar
  23. 23.
    Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003;107:1359–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 2002;105:788–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Hedman M, Hartikainen J, Syvanne M, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003;107:2677–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Pislaru S, Janssens SP, Gersh BJ, et al. Defining gene transfer before expecting gene therapy: putting the horse before the cart. Circulation 2002;106:631–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Kass-Eisler A, Falck-Pedersen E, Alvira M, et al. Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. Proc Natl Acad Sci U S A 1993;90:11498–502.PubMedCrossRefGoogle Scholar
  28. 28.
    Herschman HR. Molecular imaging: looking at problems, seeing solutions. Science 2003;302:605–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Kung HF, Kung MP, Choi SR. Radiopharmaceuticals for singlephoton emission computed tomography brain imaging. Semin Nucl Med 2003;33:2–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Schelbert HR 18F-deoxyglucose and the assessment of myocardial viability. Semin Nucl Med 2002;32:60–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Shi N, Boado RJ, Pardridge WM. Antisense imaging of gene expression in the brain in vivo. Proc Natl Acad Sci U S A 2000;97:14709–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Tavitian B, Terrazzino S, Kuhnast B, et al. In vivo imaging of oligonucleotides with positron emission tomography. Nat Med 1998;4:467–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Blasberg RG, Tjuvajev JG. Molecular-genetic imaging: current and future perspectives. J Clin Invest 2003;111:1620–9.PubMedGoogle Scholar
  34. 34.
    Tjuvajev JG, Finn R, Watanabe K, et al. Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy. Cancer Res 1996;56:4087–95.PubMedGoogle Scholar
  35. 35.
    Gambhir SS, Barrio JR, Wu L, et al. Imaging of adenoviraldirected herpes simplex virus type 1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir. J Nucl Med 1998;39:2003–11.PubMedGoogle Scholar
  36. 36.
    Gambhir SS, Bauer E, Black ME, et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc Natl Acad Sci U S A 2000;97:2785–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Min JJ, Iyer M, Gambhir SS. Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection. Eur J Nucl Med Mol Imaging 2003;30:1547–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Missale C, Nash SR, Robinson SW, et al. Dopamine receptors: from structure to function. Physiol Rev 1998;78:189–225.PubMedGoogle Scholar
  39. 39.
    MacLaren DC, Gambhir SS, Satyamurthy N, et al. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther 1999;6:785–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Zinn KR, Buchsbaum DJ, Chaudhuri TR, et al. Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with 99mTc or 188Re. J Nucl Med 2000;41:887–95.PubMedGoogle Scholar
  41. 41.
    Kaminsky SM, Levy O, Salvador C, et al. The Na/I- symporter of the thyroid gland. Soc Gen Physiol Ser 1993;48:251–62.PubMedGoogle Scholar
  42. 42.
    Groot-Wassink T, Aboagye EO, Glaser M, et al. Adenovirus biodistribution and noninvasive imaging of gene expression in vivo by positron emission tomography using human sodium/iodide symporter as reporter gene. Hum Gene Ther 2002;13:1723–35.PubMedCrossRefGoogle Scholar
  43. 43.
    Bogdanov A, Weissleder R. In vivo imaging of gene delivery and expression. Trends Biotechnol 2002;20:S11-S18.CrossRefGoogle Scholar
  44. 44.
    Weissleder R, Moore A, Mahmood U, et al. In vivo magnetic resonance imaging of transgene expression. Nat Med 2000;6:351–55.PubMedCrossRefGoogle Scholar
  45. 45.
    Ichikawa T, Hogemann D, Saeki Y, et al. MRI of transgene expression: correlation to therapeutic gene expression. Neoplasia 2002;4:523–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Allport JR, Weissleder R. In vivo imaging of gene and cell therapies. Exp Hematol 2001;29:1237–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Contag PR, Olomu IN, Stevenson DK, et al. Bioluminescent indicators in living mammals. Nat Med 1998;4:245–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Stephens DJ, Allan VJ. Light microscopy techniques for live cell imaging. Science 2003;300:82–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Choy G, O’Connor S, Diehn FE, et al. Comparison of noninvasive fluorescent and bioluminescent small animal optical imaging. Biotechniques 2003;35:1022–6, 1028–30.PubMedGoogle Scholar
  50. 50.
    Wu JC, Sundaresan G, Iyer M, et al. Noninvasive optical imaging of firefly luciferase reporter gene expression in skeletal muscles of living mice. Mol Ther 2001;4:297–306.PubMedCrossRefGoogle Scholar
  51. 51.
    Cherry SR, Gambhir SS. Use of positron emission tomography in animal research. ILAR J 2001;42:219–32.PubMedGoogle Scholar
  52. 52.
    Schelbert HR, Inubushi M, Ross RS. PET imaging in small animals. J Nucl Cardiol 2003;10:513–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Tai YC, Chatziioannou AF, Yang Y, et al. MicroPET II: design, development and initial performance of an improved microPET scanner for small-animal imaging. Phys Med Biol 2003;48:1519–37.PubMedCrossRefGoogle Scholar
  54. 54.
    Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003;17:545–80.PubMedCrossRefGoogle Scholar
  55. 55.
    Jacobs A, Voges J, Reszka R, et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 2001;358:727–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Yaghoubi S, Barrio JR, Dahlbom M, et al. Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med 2001;42:1225–34.PubMedGoogle Scholar
  57. 57.
    Wu JC, Inubushi M, Sundaresan G, et al. Optical imaging of cardiac reporter gene expression in living rats. Circulation 2002; 105:1631–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Wu JC, Inubushi M, Sundaresan G, et al. Positron emission tomography imaging of cardiac reporter gene expression in living rats. Circulation 2002;106:180–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Inubushi M, Wu JC, Gambhir SS, et al. Positron-emission tomography reporter gene expression imaging in rat myocardium. Circulation 2003;107:326–32.PubMedCrossRefGoogle Scholar
  60. 60.
    Su H, Lu R, Kan YW. Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc Natl Acad Sci U S A 2000;97:13801–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Boecker W, Bernecker OY, Wu J, et al. Cardiac specific gene expression facilitated by an enhanced myosin light chain promoter. Molecular Imaging 2004, in press.Google Scholar
  62. 62.
    Bengel FM, Anton M, Richter T, et al. Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 2003;108:2127–33.PubMedCrossRefGoogle Scholar
  63. 63.
    Tjuvajev JG, Doubrovin M, Akhurst T, et al. Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression. J Nucl Med 2002;43:1072- 83.PubMedGoogle Scholar
  64. 64.
    Miyagawa M, Simoes MV, Stadele C, et al. Comparison of two HSV1-tk-based approaches for PET imaging of cardiac reporter gene expression [abstract]. Circulation 2003;108:348.CrossRefGoogle Scholar
  65. 65.
    Chen IY, Wu JC, Min JJ, et al. Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation 2004;109:1415–200.PubMedCrossRefGoogle Scholar
  66. 66.
    Yu Y, Annala AJ, Barrio JR, et al. Quantification of target gene expression by imaging reporter gene expression in living animals. Nat Med 2000;6:933–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Chappell SA, Edelman GM, Mauro VP. A 9-nt segment of a cellular mRNA can function as an internal ribosome entry site (IRES) and when present in linked multiple copies greatly enhances IRES activity. Proc Natl Acad Sci U S A 2000;97:1536–41.PubMedCrossRefGoogle Scholar
  68. 68.
    Yaghoubi SS, Wu L, Liang Q, et al. Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors. Gene Ther 2001;8:1072–800.PubMedCrossRefGoogle Scholar
  69. 69.
    Ray P, De A, Min JJ, Tsien RY, Gambhir SS. Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res 2004;64:1323–30.PubMedCrossRefGoogle Scholar
  70. 70.
    Sun X, Annala AJ, Yaghoubi SS, et al. Quantitative imaging of gene induction in living animals. Gene Ther 2001;8:1572–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Wu JC, Chen IY, Wang Y, et al. Molecular imaging of the kinetics of VEGF gene expression in ischemic myocardium. Circulation 2004, in press.Google Scholar
  72. 72.
    Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078–83.PubMedCrossRefGoogle Scholar
  73. 73.
    Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361:45–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Orlic D, Hill JM, Arai AE. Stem cells for myocardial regeneration. Circ Res 2002;91:1092–102.PubMedCrossRefGoogle Scholar
  76. 76.
    Reinlib L, Field L. Cell transplantation as future therapy for cardiovascular disease? A workshop of the National Heart, Lung, and Blood Institute. Circulation 2000;101:E182–7.PubMedGoogle Scholar
  77. 77.
    Aicher A, Brenner W, Zuhayra M, et al. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 2003;107:2134–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Kraitchman DL, Heldman AW, Atalar E, et al. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003;107:2290–3.PubMedCrossRefGoogle Scholar
  79. 79.
    Wu JC, Chen IY, Sundaresan G, et al. Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation 2003; 108:1302–5.PubMedCrossRefGoogle Scholar
  80. 80.
    Murry CE, Wiseman RW, Schwartz SM, et al. Skeletal myoblast transplantation for repair of myocardial necrosis. J Clin Invest 1996;98:2512–23.PubMedCrossRefGoogle Scholar
  81. 81.
    Zhang M, Methot D, Poppa V, et al. Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 2001;33:907–21.PubMedCrossRefGoogle Scholar
  82. 82.
    Muller-Ehmsen J, Whittaker P, Kloner RA, et al. Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J Mol Cell Cardiol 2002;34:107–16.PubMedCrossRefGoogle Scholar
  83. 83.
    Schwarz ER, Speakman MT, Patterson M, et al. Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat—angiogenesis and angioma formation. J Am Coll Cardiol 2000;35:1323–30.PubMedCrossRefGoogle Scholar
  84. 84.
    Paulmurugan R, Umezawa Y, Gambhir SS. Noninvasive imaging of protein-protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc Natl Acad Sci U S A 2002;99:15608–13.PubMedCrossRefGoogle Scholar
  85. 85.
    Sangiorgi F. Manipulating the mouse genome: approaches and applications. J Nucl Cardiol 2001;8:591–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Zhang W, Feng JQ, Harris SE, et al. Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression. Transgenic Res 2001;10:423–34.PubMedCrossRefGoogle Scholar
  87. 87.
    Green LA, Yap CS, Nguyen K, et al. Indirect monitoring of endogenous gene expression by positron emission tomography (PET) imaging of reporter gene expression in transgenic mice. Mol Imaging Biol 2002;4:71–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Ray P, Wu AM, Gambhir SS. Optical bioluminescence and positron emission tomography imaging of a novel fusion reporter gene in tumor xenografts of living mice. Cancer Res 2003;63:1160–55.PubMedGoogle Scholar

Copyright information

© American Society of Nuclear Cardiology 2004

Authors and Affiliations

  • Joseph C. Wu
    • 1
    • 2
    • 3
  • Jeffrey R. Tseng
    • 2
    • 3
  • Sanjiv S. Gambhir
    • 2
    • 3
    • 4
  1. 1.Department of MedicineDivision of CardiologyLos Angeles
  2. 2.Department of RadiologyDivision of Nuclear MedicineLos Angeles
  3. 3.Bio-X ProgramStanford University School of MedicineStanford
  4. 4.Stanford University School of MedicineDepartment of Medicine, Division of Cardiology and Department of RadiologyStanford

Personalised recommendations