Current Cardiology Reports

, 16:521

Will 18F-Sodium Fluoride PET-CT Imaging Be the Magic Bullet for Identifying Vulnerable Coronary Atherosclerotic Plaques?

  • Nikhil V. Joshi
  • Alex Vesey
  • David E. Newby
  • Marc R. Dweck
Nuclear Cardiology (V Dilsizian, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nuclear Cardiology


Myocardial infarction remains the commonest cause of premature death worldwide with coronary atherosclerotic plaque rupture often initiating the event. Despite an ever-expanding repertoire of cardiovascular imaging techniques, the race is still on to identify atherosclerotic lesions at high-risk of rupture: the so-called vulnerable plaque. Conventional imaging modalities such as stress testing and coronary angiography have consistently failed to identify such plaques, leading to the increasing appreciation that plaque rupture relates to factors other than just the degree of luminal stenosis. Indeed the focus has recently shifted to molecular imaging, in an attempt to directly target the pathological disease processes leading to rupture and thereby localize high-risk lesions. Histological data indicate that inflammation, necrosis and early stage microcalcification are key imaging targets by which to achieve this aim. Here, we discuss how these processes are related, focusing on the rationale and evidence supporting 18F-fluoride positron emission tomography as a novel non-invasive imaging technique for the identification of vulnerable atherosclerotic plaque.


Positron emission tomography Computed tomography 18F-fluoride PET-CT imaging Coronary atherosclerosis Plaques 


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation. 2003;108(14):1664–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Calvert PA, Obaid DR, O'Sullivan M, Shapiro LM, McNab D, Densem CG, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study. JACC Cardiovasc Imaging. 2011;4(8):894–901.PubMedCrossRefGoogle Scholar
  3. 3.••
    Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364(3):226–35. This landmark study looked at the natural history of coronary atherosclerotic plaques using radiofrequency intravascular ultrasound and provided key pathological insights into our understanding of coronary disease.PubMedCrossRefGoogle Scholar
  4. 4.
    Rogers IS, Nasir K, Figueroa AL, Cury RC, Hoffmann U, Vermylen DA, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging. 2010;3(4):388–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79(4):733–43.PubMedCrossRefGoogle Scholar
  6. 6.
    Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336(18):1276.PubMedCrossRefGoogle Scholar
  7. 7.
    Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103(7):934–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J. 2013;34(10):719–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30(7):1282–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(8 Suppl):C13–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20(5):1262–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503–16.PubMedCrossRefGoogle Scholar
  13. 13.
    Kato K, Yonetsu T, Kim SJ, Xing L, Lee H, McNulty I, et al. Nonculprit plaques in patients with acute coronary syndromes have more vulnerable features compared with those with non-acute coronary syndromes: a 3-vessel optical coherence tomography study. Circ Cardiovasc Imaging. 2012;5(4):433–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Aikawa E, Nahrendorf M, Figueiredo JL, Swirski FK, Shtatland T, Kohler RH, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116(24):2841–50.PubMedCrossRefGoogle Scholar
  15. 15.
    Otsuka F, Finn AV, Virmani R. Do vulnerable and ruptured plaques hide in heavily calcified arteries? Atherosclerosis. 2013;229(1):34–7.PubMedCrossRefGoogle Scholar
  16. 16.
    New SE, Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 2011;108(11):1381–91.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation. 2000;102(21):2636–42.PubMedCrossRefGoogle Scholar
  18. 18.
    Radcliff K, Tang TB, Lim J, Zhang Z, Abedin M, Demer LL, et al. Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways. Circ Res. 2005;96(4):398–400.PubMedCrossRefGoogle Scholar
  19. 19.
    Demer LL, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation. 2008;117(22):2938–48.PubMedCrossRefGoogle Scholar
  20. 20.
    Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res. 2000;87(11):1055–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Shanahan CM. Inflammation ushers in calcification: a cycle of damage and protection? Circulation. 2007;116(24):2782–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Bobryshev YV, Killingsworth MC, Huynh TG, Lord RS, Grabs AJ, Valenzuela SM. Are calcifying matrix vesicles in atherosclerotic lesions of cellular origin? Basic Res Cardiol. 2007;102(2):133–43.PubMedCrossRefGoogle Scholar
  23. 23.
    Golub EE. Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol. 2011;33(5):409–17.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Lardinois D, Weder W, Hany TF, Kamel EM, Korom S, Seifert B, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348(25):2500–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for bone scanning. J Nucl Med. 1962;3:332–4.PubMedGoogle Scholar
  26. 26.
    Blau M, Ganatra R, Bender MA. 18F-fluoride for bone imaging. Semin Nucl Med. 1972;2(1):31–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Hawkins RA, Choi Y, Huang SC, Hoh CK, Dahlbom M, Schiepers C, et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med. 1992;33(5):633–42.PubMedGoogle Scholar
  28. 28.
    Blake GM, Park-Holohan SJ, Cook GJ, Fogelman I. Quantitative studies of bone with the use of 18F-fluoride and 99mTc-methylene diphosphonate. Semin Nucl Med. 2001;31(1):28–49.PubMedCrossRefGoogle Scholar
  29. 29.
    Wootton R, Dore C. The single-passage extraction of 18F in rabbit bone. Clin Phys Physiol Meas. 1986;7(4):333–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Hoh CK, Hawkins RA, Dahlbom M, Glaspy JA, Seeger LL, Choi Y, et al. Whole body skeletal imaging with [18F]fluoride ion and PET. J Comput Assist Tomogr. 1993;17(1):34–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Cook GJ, Blake GM, Marsden PK, Cronin B, Fogelman I. Quantification of skeletal kinetic indices in Paget's disease using dynamic 18F-fluoride positron emission tomography. J Bone Miner Res. 2002;17(5):854–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Installe J, Nzeusseu A, Bol A, Depresseux G, Devogelaer JP, Lonneux M. (18)F-fluoride PET for monitoring therapeutic response in Paget's disease of bone. J Nucl Med. 2005;46(10):1650–8.PubMedGoogle Scholar
  33. 33.
    Frost ML, Fogelman I, Blake GM, Marsden PK, Cook Jr G. Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis. J Bone Miner Res. 2004;19(11):1797–804.PubMedCrossRefGoogle Scholar
  34. 34.
    Messa C, Goodman WG, Hoh CK, Choi Y, Nissenson AR, Salusky IB, et al. Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endocrinol Metab. 1993;77(4):949–55.PubMedGoogle Scholar
  35. 35.
    Hsu WK, Feeley BT, Krenek L, Stout DB, Chatziioannou AF, Lieberman JR. The use of 18F-fluoride and 18F-FDG PET scans to assess fracture healing in a rat femur model. Eur J Nucl Med Mol Imaging. 2007;34(8):1291–301.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Schiepers C, Broos P, Miserez M, Bormans G, De Roo M. Measurement of skeletal flow with positron emission tomography and 18F-fluoride in femoral head osteonecrosis. Arch Orthop Trauma Surg. 1998;118(3):131–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Petren-Mallmin M, Andreasson I, Ljunggren O, Ahlstrom H, Bergh J, Antoni G, et al. Skeletal metastases from breast cancer: uptake of 18F-fluoride measured with positron emission tomography in correlation with CT. Skelet Radiol. 1998;27(2):72–6.CrossRefGoogle Scholar
  38. 38.
    Schirrmeister H, Guhlmann A, Kotzerke J, Santjohanser C, Kuhn T, Kreienberg R, et al. Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography. J Clin Oncol. 1999;17(8):2381–9.PubMedGoogle Scholar
  39. 39.
    Hetzel M, Arslandemir C, Konig HH, Buck AK, Nussle K, Glatting G, et al. F-18 NaF PET for detection of bone metastases in lung cancer: accuracy, cost-effectiveness, and impact on patient management. J Bone Miner Res. 2003;18(12):2206–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. 2006;47(2):287–97.PubMedGoogle Scholar
  41. 41.
    Beheshti M, Vali R, Waldenberger P, Fitz F, Nader M, Loidl W, et al. Detection of bone metastases in patients with prostate cancer by 18F fluorocholine and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging. 2008;35(10):1766–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Rey C, Combes C, Drouet C, Glimcher MJ. Bone mineral: update on chemical composition and structure. Osteoporos Int. 2009;20(6):1013–21.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Agnese Irkle JLB, Skepper JN, Dweck MR, Joshi FR, Vesey AT, Bennett M, et al. 18F-NaF - a Specific Marker for Vascular Calcification in Atherosclerosis. Circulation. 2013;128:A17385.Google Scholar
  44. 44.
    Derlin T, Richter U, Bannas P, Begemann P, Buchert R, Mester J, et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med. 2010;51(6):862–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Derlin T, Toth Z, Papp L, Wisotzki C, Apostolova I, Habermann CR, et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J Nucl Med. 2011;52(7):1020–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Janssen T, Bannas P, Herrmann J, Veldhoen S, Busch JD, Treszl A, et al. Association of linear (18)F-sodium fluoride accumulation in femoral arteries as a measure of diffuse calcification with cardiovascular risk factors: A PET/CT study. J Nucl Cardiol. 2013;20(4):569–77.PubMedCrossRefGoogle Scholar
  47. 47.
    Beheshti M, Saboury B, Mehta NN, Torigian DA, Werner T, Mohler E, et al. Detection and global quantification of cardiovascular molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography–a novel concept. Hell J Nucl Med. 2011;14(2):114–20.PubMedGoogle Scholar
  48. 48.••
    Dweck MR, Jones C, Joshi N, Fletcher AM, Richardson H, White A, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2011. doi:10.1161/CIRCULATIONAHA.111.051052. This important study looks at 18F-fluoride uptake in aortic valve disease.Google Scholar
  49. 49.
    Dweck MR, Khaw HJ, Sng GK, Luo EL, Baird A, Williams MC, et al. Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation? Eur Heart J. 2013;34(21):1567–74.PubMedCrossRefGoogle Scholar
  50. 50.
    Dweck MR, Jenkins WS, Vesey AT, Pringle MA, Chin CW, Malley TS, et al. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging. 2014;7(2):371–8.PubMedCrossRefGoogle Scholar
  51. 51.••
    Dweck MR, Chow MW, Joshi NV, Williams MC, Jones C, Fletcher AM, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol. 2012;59(17):1539–48. We first described the coronary uptake of 18F-fluoride in patients with or without aortic stenosis in this important paper.PubMedCrossRefGoogle Scholar
  52. 52.••
    Joshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH, et al. F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2013. doi:10.1016/S0140-6736(13)61754-7. In this paper, we show that 18F-fluoride can identify ruptured and high risk plaques in patients with myocardial infarction and stable angina. Furthermore, we characterise these plaques with intravascular imaging in patients with stable angina and with histology in patients undergoing carotid endartrectomy.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nikhil V. Joshi
    • 1
    • 2
  • Alex Vesey
    • 1
  • David E. Newby
    • 1
  • Marc R. Dweck
    • 1
  1. 1.Centre for Cardiovascular Science / Clinical Research Imaging Centre/ Edinburgh Heart CentreUniversity of EdinburghEdinburghUK
  2. 2.University/BHF Centre for Cardiovascular ScienceEdinburghUK

Personalised recommendations