Semin Thromb Hemost 2007; 33(2): 151-158
DOI: 10.1055/s-2007-969028
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Where Is the Trace? Molecular Imaging of Vulnerable Atherosclerotic Plaques

Harald Langer1 , Tanja Schönberger1 , Boris Bigalke1 , Meinrad Gawaz1
  • 1Medizinische Klinik III, Universitätsklinikum Tübingen, Tübingen, Germany
Further Information

Publication History

Publication Date:
06 March 2007 (online)

ABSTRACT

Serious cardiovascular events frequently arise from rupture of vulnerable atherosclerotic plaques. Not infrequently, these plaques are clinically silent and suddenly cause acute complications such as myocardial infarction, which in a high percentage are fatal. Thus, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in clinical medicine. This review highlights noninvasive scintigraphic techniques, which use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing their biological activity. One major principle is the molecular imaging of inflammation with radionuclide tracers, including detection of metabolic activity, chemotaxis, cell recruitment, and lipoprotein enrichment. Additional studies focus on visualization of apoptosis, angiogenesis, or proteolysis. A central feature of plaque vulnerability is its thrombogenicity. Therefore, detection of thrombogenic plaques is another promising principle of molecular imaging. If a reliable protocol to image vulnerable plaques, which are prone to rupture, can be established and introduced into clinical practice, the required measures such as atheroprotective medication or revascularization could be undertaken to prevent serious cardiovascular events.

REFERENCES

  • 1 Myerburg R J, Interian Jr A, Mitrani R M, Kessler K M, Castellanos A. Frequency of sudden cardiac death and profiles of risk.  Am J Cardiol. 1997;  80 10F-19F
  • 2 Nissen S E, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications.  Circulation. 2001;  103 604-616
  • 3 Schroeder S, Kopp A F, Baumbach A et al.. Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography.  J Am Coll Cardiol. 2001;  37 1430-1435
  • 4 Schmermund A, Erbel R. Unstable coronary plaque and its relation to coronary calcium.  Circulation. 2001;  104 1682-1687
  • 5 Naghavi M, Libby P, Falk E et al.. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II.  Circulation. 2003;  108 1772-1778
  • 6 Ross R. Atherosclerosis-an inflammatory disease.  N Engl J Med. 1999;  340 115-126
  • 7 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420 868-874
  • 8 Ogawa M, Ishino S, Mukai T et al.. (18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study.  J Nucl Med. 2004;  45 1245-1250
  • 9 Rudd J H, Warburton E A, Fryer T D et al.. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.  Circulation. 2002;  105 2708-2711
  • 10 Gawaz M, Neumann F J, Dickfeld T et al.. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells.  Circulation. 1998;  98 1164-1171
  • 11 Ohtsuki K, Hayase M, Akashi K, Kopiwoda S, Strauss H W. Detection of monocyte chemoattractant protein-1 receptor expression in experimental atherosclerotic lesions: an autoradiographic study.  Circulation. 2001;  104 203-208
  • 12 Virgolini I, Muller C, Fitscha P, Chiba P, Sinzinger H. Radiolabelling autologous monocytes with 111-indium-oxine for reinjection in patients with atherosclerosis.  Prog Clin Biol Res. 1990;  355 271-280
  • 13 Haubner R, Wester H J, Burkhart F et al.. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics.  J Nucl Med. 2001;  42 326-336
  • 14 Janssen M L, Oyen W J, Dijkgraaf I et al.. Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model.  Cancer Res. 2002;  62 6146-6151
  • 15 Matter C M, Schuler P K, Alessi P et al.. Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin.  Circ Res. 2004;  95 1225-1233
  • 16 Virgolini I, Rauscha F, Lupattelli G et al.. Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage.  Eur J Nucl Med. 1991;  18 948-951
  • 17 Virgolini I, Angelberger P, O'Grady J, Sinzinger H. Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage.  Eur J Nucl Med. 1991;  18 944-947
  • 18 Tsimikas S, Palinski W, Witztum J L. Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice.  Arterioscler Thromb Vasc Biol. 2001;  21 95-100
  • 19 Tsimikas S. Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies.  Am J Cardiol. 2002;  90 22L-27L
  • 20 Tsimikas S, Shortal B P, Witztum J L, Palinski W. In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression.  Arterioscler Thromb Vasc Biol. 2000;  20 689-697
  • 21 Iuliano L, Signore A, Vallabajosula S et al.. Preparation and biodistribution of 99m technetium labelled oxidized LDL in man.  Atherosclerosis. 1996;  126 131-141
  • 22 Geng Y J, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme.  Am J Pathol. 1995;  147 251-266
  • 23 Thomas W A, Scott R F, Florentin R A, Reiner J M, Lee K T. Population dynamics of arterial cells during atherogenesis. XI. Slowdown in multiplication and death rates of lesion smooth muscle cells in swine during the period 105-165 days after balloon endothelial cell denudation followed by a hyperlipidemic diet.  Exp Mol Pathol. 1981;  35 153-162
  • 24 Thomas W A, Kim D N, Lee K T, Reiner J M, Schmee J. Population dynamics of arterial cells during atherogenesis. XIII. Mitogenic and cytotoxic effects of a hyperlipidemic (HL) diet on cells in advanced lesions in the abdominal aortas of swine fed an HL diet for 270-345 days.  Exp Mol Pathol. 1983;  39 257-270
  • 25 Johnson L L, Schofield L, Donahay T, Narula N, Narula J. 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries.  J Nucl Med. 2005;  46 1186-1193
  • 26 Narula J, Acio E R, Narula N et al.. Annexin-V imaging for noninvasive detection of cardiac allograft rejection.  Nat Med. 2001;  7 1347-1352
  • 27 Hofstra L, Liem I H, Dumont E A et al.. Visualisation of cell death in vivo in patients with acute myocardial infarction.  Lancet. 2000;  356 209-212
  • 28 Kolodgie F D, Petrov A, Virmani R et al.. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque.  Circulation. 2003;  108 3134-3139
  • 29 Schafers M, Riemann B, Kopka K et al.. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo.  Circulation. 2004;  109 2554-2559
  • 30 Langer H, Gawaz M. Molecular imaging of vulnerable atherosclerotic plaques.  Future Cardiology. 2006;  2 113-122
  • 31 Minar E, Ehringer H, Dudczak R et al.. Indium-111-labeled platelet scintigraphy in carotid atherosclerosis.  Stroke. 1989;  20 27-33
  • 32 Moriwaki H, Matsumoto M, Handa N et al.. Functional and anatomic evaluation of carotid atherothrombosis. A combined study of indium 111 platelet scintigraphy and B-mode ultrasonography.  Arterioscler Thromb Vasc Biol. 1995;  15 2234-2240
  • 33 Smyth J V, Dodd P D, Walker M G. Indium-111 platelet scintigraphy in vascular disease.  Br J Surg. 1995;  82 588-595
  • 34 Vallabhajosula S. Technetium-99m-P748, platelet specific techtide for imaging arterial thrombus: preclinical studies in a canine model of intra-arterial thrombus.  J Nucl Med. 2005;  7 152(abst)
  • 35 Cerqueira M D, Stratton J R, Vracko R, Schaible T F, Ritchie J L. Noninvasive arterial thrombus imaging with 99mTc monoclonal antifibrin antibody.  Circulation. 1992;  85 298-304
  • 36 Greco C, Di Loreto M, Ciavolella M et al.. Immunodetection of human atherosclerotic plaque with 125I-labeled monoclonal antifibrin antibodies.  Atherosclerosis. 1993;  100 133-139
  • 37 Clemetson K J, Clemetson J M. Platelet collagen receptors.  Thromb Haemost. 2001;  86 189-197
  • 38 Nieswandt B, Watson S P. Platelet-collagen interaction: is GPVI the central receptor?.  Blood. 2003;  102 449-461
  • 39 Massberg S, Konrad I, Bultmann A et al.. Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo.  FASEB J. 2004;  18 397-399
  • 40 Moers A, Nieswandt B, Massberg S et al.. G13 is an essential mediator of platelet activation in hemostasis and thrombosis.  Nat Med. 2003;  9 1418-1422
  • 41 Gawaz M, Konrad I, Hauser A I et al.. Non-invasive imaging of glycoprotein VI binding to injured arterial lesions.  Thromb Haemost. 2005;  93 910-913
  • 42 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes (1).  N Engl J Med. 1992;  326 242-250
  • 43 Farb A, Burke A P, Tang A L et al.. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death.  Circulation. 1996;  93 1354-1363

Harald LangerM.D. 

Medizinische Klinik III, Universitätsklinikum Tübingen

Otfried-Müller Str. 10, 72076 Tübingen, Germany

Email: harald.langer@med.uni-tuebingen.de