European Radiology

, Volume 17, Issue 6, pp 1422–1432 | Cite as

Molecular cardiovascular imaging using scintigraphic methods

  • Lars Stegger
  • Klaus Schäfers
  • Klaus Kopka
  • Stefan Wagner
  • Sven Hermann
  • Peter Kies
  • Marilyn Law
  • Otmar Schober
  • Michael Schäfers
Molecular Imaging

Abstract

Molecular cardiovascular imaging plays an increasingly important role both in basic research and in clinical diagnosis. Scintigraphic methods have long been used to study pathophysiological changes on a cellular and molecular level, and they are likely to remain important molecular imaging modalities in the foreseeable future. This article provides an overview over current developments in cardiovascular molecular imaging using scintigraphic methods. The focus lies on imaging of cardiac innervation, plaque instability, hypoxia and angiogenesis, gene expression and stem and progenitor cell migration and proliferation.

Keywords

Molecular imaging Scintigraphic Cardiovascular SPECT PET 

Notes

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich SFB 656 MoBIL, Münster, Germany (Projects A1-A5, B3, C1, C2, PM3).

References

  1. 1.
    Blumgart HL, Yens OC (1927) Studies on the velocity of blood flow: I. The method utilized. J Clin Invest 4:1–13PubMedCrossRefGoogle Scholar
  2. 2.
    Schäfers KP, Stegger L, Barnard C et al (2005) ECG-triggered high-resolution positron emission tomography: a breakthrough in cardiac molecular imaging of mice. Eur J Nucl Med Mol Imaging 32:383PubMedCrossRefGoogle Scholar
  3. 3.
    Assmann G, Cullen P, Schulte H (2002) Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Münster (PROCAM) study. Circulation 105:310–315PubMedCrossRefGoogle Scholar
  4. 4.
    Vanzetto G, Ormezzano O, Fagret D, Comet M, Denis B, Machecourt J (1999) Long-term additive prognostic value of thallium-201 myocardial perfusion imaging over clinical and exercise stress test in low to intermediate risk patients: study in 1137 patients with 6-year follow-up. Circulation 100:1521–1527PubMedGoogle Scholar
  5. 5.
    Hachamovitch R, Berman DS, Kiat H et al (1996) Exercise myocardial perfusion SPECT in patients without known coronary artery disease: incremental prognostic value and use in risk stratification. Circulation 93:905–914PubMedGoogle Scholar
  6. 6.
    Beller GA, Bergmann SR (2004) Myocardial perfusion imaging agents: SPECT and PET. J Nucl Cardiol 11:71–86PubMedCrossRefGoogle Scholar
  7. 7.
    Germano G, Kiat H, Kavanagh PB et al (1995) Automatic quantitation of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 36:2138–2147PubMedGoogle Scholar
  8. 8.
    Stegger L, Biedenstein S, Schäfers KP, Schober O, Schäfers MA (2001) Elastic surface contour detection for the measurement of ejection fraction in myocardial perfusion SPET. Eur J Nucl Med 28:48–55PubMedCrossRefGoogle Scholar
  9. 9.
    Sharir T, Germano G, Kavanagh PB et al (1999) Incremental prognostic value of post-stress left ventricular ejection fraction and volume by gated myocardial perfusion single photon emission computed tomography. Circulation 100:1035–1042PubMedGoogle Scholar
  10. 10.
    Schelbert HR (2002) 18F-deoxyglucose and the assessment of myocardial viability. Semin Nucl Med 32:60–69PubMedCrossRefGoogle Scholar
  11. 11.
    Stegger L, Schäfers KP, Flögel U et al (2005) Monitoring left ventricular dilation in mice with PET. J Nucl Med 46:1516–1521PubMedGoogle Scholar
  12. 12.
    Tamaki N, Morita K, Kuge Y, Tsukamoto E (2000) The role of fatty acids in cardiac imaging. J Nucl Med 41:1525–1534PubMedGoogle Scholar
  13. 13.
    Schäfers M, Dutka D, Rhodes CG et al (1998) Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy. Circ Res 82:57–62PubMedGoogle Scholar
  14. 14.
    Wichter T, Schäfers M, Rhodes CG et al (2000) Abnormalities of cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy: quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic beta-adrenergic receptor density with positron emission tomography. Circulation 101:1552–1558PubMedGoogle Scholar
  15. 15.
    Schäfers M, Lerch H, Wichter T et al (1998) Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 32:181–186PubMedCrossRefGoogle Scholar
  16. 16.
    Kies P, Wichter T, Schäfers M et al (2004) Abnormal myocardial presynaptic norepinephrine recycling in patients with Brugada syndrome. Circulation 110:3017–3022PubMedCrossRefGoogle Scholar
  17. 17.
    de Jong RM, Willemsen AT, Slart RH et al (2005) Myocardial beta-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388. Eur J Nucl Med Mol Imaging 32:443–447PubMedCrossRefGoogle Scholar
  18. 18.
    Wagner S, Law MP, Riemann B et al (2006) Synthesis of a F-18-labelled high affinity beta1-adrenoceptor PET radioligand based on ICI 89, 406. J Label Compd Radiopharm 49:177–195CrossRefGoogle Scholar
  19. 19.
    Law MP, Osman S, Pike VW et al (2000) Evaluation of [11C]GB67, a novel radioligand for imaging myocardial alpha 1-adrenoceptors with positron emission tomography. Eur J Nucl Med 27:7–17PubMedCrossRefGoogle Scholar
  20. 20.
    Inoue H, Zipes DP (1987) Results of sympathetic denervation in the canine heart: supersensitivity that may be arrhythmogenic. Circulation 75:877–887PubMedGoogle Scholar
  21. 21.
    Inobe Y, Kugiyama K, Miyagi H et al (1997) Longlasting abnormalities in cardiac sympathetic nervous system in patients with coronary spastic angina: quantitative analysis with iodine 123 metaiodobenzylguanidine myocardial scintigraphy. Am Heart J 134:112–118PubMedCrossRefGoogle Scholar
  22. 22.
    Wilson RF, Laxson DD, Christensen BV, McGinn AL, Kubo SH (1993) Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation. Circulation 88:165–171PubMedGoogle Scholar
  23. 23.
    Yamada T, Shimonagata T, Fukunami M et al (2003) Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure: a prospective study. J Am Coll Cardiol 41:231–238PubMedCrossRefGoogle Scholar
  24. 24.
    Paul M, Schäfers M, Kies P et al (2006) Impact of sympathetic innervation on recurrent life-threatening arrhythmias in the follow-up of patients with idiopathic ventricular fibrillation. Eur J Nucl Med Mol Imaging 33:866–870PubMedCrossRefGoogle Scholar
  25. 25.
    Nakata T, Wakabayashi T, Kyuma M, Takahashi T, Tsuchihashi K, Shimamoto K (2004) Cardiac metaiodobenzylguanidine activity can predict the long-term efficacy of angiotensin-converting enzyme inhibitors and/or beta-adrenoceptor blockers in patients with heart failure. Eur J Nucl Med Mol Imaging 32:186–194PubMedCrossRefGoogle Scholar
  26. 26.
    Lekakis J, Prassopoulos V, Athanassiadis P, Kostamis P, Moulopoulos S (1996) Doxorubicin-induced cardiac neurotoxicity: study with iodine 123-labeled metaiodobenzylguanidine scintigraphy. J Nucl Cardiol 3:37–41PubMedCrossRefGoogle Scholar
  27. 27.
    Delforge J, Le Guludec D, Syrota A et al (1993) Quantification of myocardial muscarinic receptors with PET in humans. J Nucl Med 34:981–991PubMedGoogle Scholar
  28. 28.
    Le Guludec D, Cohen-Solal A, Delforge J, Delahaye N, Syrota A, Merlet P (1997) Increased myocardial muscarinic receptor density in idiopathic dilated cardiomyopathy: an in vivo PET study. Circulation 96:3416–3422PubMedGoogle Scholar
  29. 29.
    Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation 92:657–671PubMedGoogle Scholar
  30. 30.
    Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC (2004) Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 29:210–215CrossRefGoogle Scholar
  31. 31.
    Rudd JH, Warbourton EA, Fryer TD et al (2002) Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 105:2708–2711PubMedCrossRefGoogle Scholar
  32. 32.
    Kopka K, Breyholz HJ, Wagner S et al (2004) Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. Nucl Med Biol 31:257–267PubMedCrossRefGoogle Scholar
  33. 33.
    Schäfers M, Riemann B, Kopka K et al (2004) Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 109:2554–2559PubMedCrossRefGoogle Scholar
  34. 34.
    Furumoto S, Takashima K, Kubuta K, Ido T, Iwata R, Fukuda H (2003) Tumor detection using 18F-labeled matrix metalloproteinase-2 inhibitor. Nucl Med Biol 30:119–125PubMedCrossRefGoogle Scholar
  35. 35.
    Breyholz H-J, Schäfers M, Wagner S et al (2005) C-5-disubstituted barbiturates as potential molecular probes for noninvasive matrix metalloproteinase imaging. J Med Chem 48:3400–3409PubMedCrossRefGoogle Scholar
  36. 36.
    Kolodgie FD, Petrov A, Virmani R et al (2003) Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108:3134–3139PubMedCrossRefGoogle Scholar
  37. 37.
    Kietselaer BL, Reutelingsperger CP, Heidendal GA et al (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 350:1472–1473PubMedCrossRefGoogle Scholar
  38. 38.
    Hartung D, Sarai M, Petrov A et al (2005) Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. J Nucl Med 46:2051–2056PubMedGoogle Scholar
  39. 39.
    Hofstra L, Liem IH, Dumont EA et al (2000) Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 356:209–212PubMedCrossRefGoogle Scholar
  40. 40.
    Narula J, Acio ER, Narula N et al (2001) Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 7:1347–1352PubMedCrossRefGoogle Scholar
  41. 41.
    Mariani G, Villa G, Rossettin PF et al (1999) Detection of acute myocardial infarction by 99mTc labeled D-glucararic acid imaging in patients with acute chest pain. J Nucl Med 54:1832–1839Google Scholar
  42. 42.
    Inoue A, Yanagisawa M, Kimura S et al (1989) The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 86:2863–2867PubMedCrossRefGoogle Scholar
  43. 43.
    Iwasa S, Fan J, Shimokama T, Nagata M, Watanabe T (1999) Increased immunoreactivity of endothelin-1 and endothelin B receptor in human atherosclerotic lesions. A possible role in atherogenesis. Atherosclerosis 146:93–100PubMedCrossRefGoogle Scholar
  44. 44.
    Johnström P, Harris NG, Fryer TD et al (2002) 18F-Endothelin-I, a positron emission tomography (PET) radioligand for the endothelin receptor system: radiosynthesis and in vivo imaging using microPET. Clin Sci 103:4S–8SPubMedGoogle Scholar
  45. 45.
    Dinkelborg LM, Duda SH, Hanke H, Tepe G, Hilger CS, Semmler W (1998) Molecular imaging of atherosclerosis using a technetium-99m-labeled endothelin derivative. J Nucl Med 39:1819–1822PubMedGoogle Scholar
  46. 46.
    Johnström P, Rudd JH, Richards HK et al (2006) Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET). Exp Biol Med 231:736–740Google Scholar
  47. 47.
    Livieratos L, Stegger L, Bloomfield PM, Schafers K, Bailey DL, Camici PG (2005) Rigid-body transformation of list-mode projection data for respiratory motion correction in cardiac PET. Phys Med Biol 50:3313–3322PubMedCrossRefGoogle Scholar
  48. 48.
    Dawood M, Lang N, Jiang X, Schafers KP (2006) Lung motion correction on respiratory gated 3-D PET/CT images. IEEE Trans Med Imaging 25:476–485PubMedCrossRefGoogle Scholar
  49. 49.
    Shelton ME, Dence CS, Hwang DR, Herrero P, Welch MJ, Bergmann SR (1990) In vivo delineation of myocardial hypoxia during coronary occlusion using fluorine-18 fluoromisonidazole and positron emission tomography: a potential approach for identification of jeopardized myocardium. J Am Coll Cardiol 16:477–485PubMedCrossRefGoogle Scholar
  50. 50.
    Fujibayashi Y, Cutler CS, Anderson CJ et al (1999) Comparative studies of Cu-64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats. Nucl Med Biol 26:117–121PubMedCrossRefGoogle Scholar
  51. 51.
    Udelson JE, Dilsizian V, Laham RJ et al (2000) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation 102:1605–1610PubMedGoogle Scholar
  52. 52.
    Henry TD, Rocha-Singh K, Isner JM et al (2001) Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary aftery disease. Am Heart J 142:872–880PubMedCrossRefGoogle Scholar
  53. 53.
    Giordano FJ, Ping P, McKirnan MD et al (1996) Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 2:534–539PubMedCrossRefGoogle Scholar
  54. 54.
    Lu E, Wagner WR, Schellenberger U et al (2003) Targeted in vivo labeling of receptors for vascular endothelial growth factor: approach to identification of ischemic tissue. Circulation 108:97–103PubMedCrossRefGoogle Scholar
  55. 55.
    Haubner R, Wester H-J, Reuning U et al (1999) Radiolabeled αvβ3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med 40:1061–1071PubMedGoogle Scholar
  56. 56.
    Beer AJ, Haubner R, Sarbia M et al (2006) Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res 12:3942–3949PubMedCrossRefGoogle Scholar
  57. 57.
    Meoli DF, Sadeghi MM, Krassilnikova S et al (2004) Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest 113:1684–1691PubMedCrossRefGoogle Scholar
  58. 58.
    Sadeghi MM, Krassilnikova S, Zhang J et al (2004) Detection of injury-induced vascular remodeling by targeting activated alpha V beta 3 integrin in vivo. Circulation 110:84–90PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang J, Krassilnikova S, Gharaei AA et al (2005) Alphavbeta3-targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study. FASEB J 19:1857–1859PubMedGoogle Scholar
  60. 60.
    Donahue JK, Kikuchi K, Sasano T (2005) Gene therapy for cardiac arrhythmias. Trends Cardiovasc Med 15:219–224PubMedCrossRefGoogle Scholar
  61. 61.
    Wu JC, Inubushi M, Sundaresan G, Schelbert HR, Gambhir SS (2002) Positron emission tomography imaging of cardiac reporter gene expression in living rats. Circulation 106:180–183PubMedCrossRefGoogle Scholar
  62. 62.
    Bengel FM, Anton M, Richter T et al (2003) Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 108:2127–2133PubMedCrossRefGoogle Scholar
  63. 63.
    Jacobs A, Voges J, Reszka R et al (2001) Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 358:727–729PubMedCrossRefGoogle Scholar
  64. 64.
    MacLaren DC, Gambhir SS, Satyamurthy N et al (1999) Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther 6:785–791PubMedCrossRefGoogle Scholar
  65. 65.
    Miyagawa M, Beyer M, Wagner B et al (2005) Cardiac reporter gene imaging using the human sodium/iodide symporter gene. Cardiovasc Res 65:195–202PubMedCrossRefGoogle Scholar
  66. 66.
    Chen IY, Wu JC, Min JJ et al (2004) Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation 109:1415–1420PubMedCrossRefGoogle Scholar
  67. 67.
    Wu JC, Chen IY, Wang Y et al (2004) Molecular imaging of the kinetics of vascular endothelial growth factor gene expression in ischemic myocardium. Circulation 110:685–691PubMedCrossRefGoogle Scholar
  68. 68.
    Orlic D, Kajstura J, Chementi S et al (2004) Bone marrow cells regenerate infarcted myocardium. Nature 428:664–668CrossRefGoogle Scholar
  69. 69.
    Aicher A, Brenner W, Zuhayra M et al (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107:2134–2139PubMedCrossRefGoogle Scholar
  70. 70.
    Wu JC, Spin JM, Cao F et al (2006) Transcriptional profiling of reporter genes used for molecular imaging of embryonic stem cell transplantation. Physiol Genomics 25:29–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Lars Stegger
    • 1
  • Klaus Schäfers
    • 1
  • Klaus Kopka
    • 1
  • Stefan Wagner
    • 1
  • Sven Hermann
    • 1
  • Peter Kies
    • 1
  • Marilyn Law
    • 1
  • Otmar Schober
    • 1
  • Michael Schäfers
    • 1
  1. 1.Department of Nuclear MedicineUniversity Hospital of MünsterMünsterGermany

Personalised recommendations