Journal of Nuclear Cardiology

, Volume 25, Issue 5, pp 1774–1783 | Cite as

In search of the vulnerable patient or the vulnerable plaque: 18F-sodium fluoride positron emission tomography for cardiovascular risk stratification

  • Jamie W. Bellinge
  • Roslyn J. Francis
  • Kamran Majeed
  • Gerald F. Watts
  • Carl J. Schultz
Review Article


Cardiovascular disease (CVD) remains a leading cause of death. Preventative therapies that reduce CVD are most effective when targeted to individuals at high risk. Current risk stratification tools have only modest prognostic capabilities, resulting in over-treatment of low-risk individuals and under-treatment of high-risk individuals. Improved methods of CVD risk stratification are required. Molecular imaging offers a novel approach to CVD risk stratification. In particular, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) has shown promise in the detection of both high-risk atherosclerotic plaque features and vascular calcification activity, which predicts future development of new vascular calcium deposits. The rate of change of coronary calcium scores, measured by serial computed tomography scans over a 2-year period, is a strong predictor of CVD risk. Vascular calcification activity, as measured with 18F-NaF PET, has the potential to provide prognostic information similar to consecutive coronary calcium scoring, with a single-time-point convenience. However, owing to the rapid motion and small size of the coronary arteries, new solutions are required to address the traditional limitations of PET imaging. Two different methods of coronary PET analysis have been independently proposed and here we compare their respective strengths, weaknesses, and the potential for clinical translation.


CAD PET image analysis molecular imaging agents diagnostic and prognostic application atherosclerosis 



18F-sodium fluoride




Positron emission tomography


Cardiovascular disease


Computed tomography


Optical coherence tomography


Intravascular ultrasound


Coronary artery calcium score



The authors wish to acknowledge James Goodchild from Royal Perth Hospital Medical Illustrations for his artistic contribution to the manuscript.


Dr. Bellinge, Prof. Watts, A/Prof. Francis and Dr. Majeed have no disclosures. Prof. Schultz reports a research grant from Abbot Vascular outside the submitted work.

Supplementary material

12350_2018_1360_MOESM1_ESM.pptx (21.5 mb)
Supplementary material 1 (PPTX 22021 kb)


  1. 1.
    World Health Organisation. Global Atlas on cardiovascular disease prevention and control. Geneva: World Health Organisation; 2011. Cited 28 May 2018.
  2. 2.
    Detrano R, Guerci AD, Carr JJ, Bild DCEE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336-45.CrossRefPubMedGoogle Scholar
  3. 3.
    Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O’Leary D, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Budoff MJ, Hokanson JE, Nasir K, Shaw LJ, Kinney GL, Chow D, et al. Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovasc Imaging 2010;3:1229-36.CrossRefPubMedGoogle Scholar
  5. 5.
    Budoff MJ, Young R, Lopez VA, Kronmal RA, Nasir K, Blumenthal RS, et al. Progression of coronary calcium and incident coronary heart disease events MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2013;61:1231-9.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Maurovich-Horvat P, Ferencik M, Voros S, Merkely B, Hoffmann U. Comprehensive plaque assessment by coronary CT angiography. Nat Rev Cardiol 2014;11:390-402.CrossRefPubMedGoogle Scholar
  7. 7.
    Fujii K, Carlier SG, Mintz GS, Takebayashi H, Yasuda T, Costa RA, et al. Intravascular ultrasound study of patterns of calcium in ruptured coronary plaques. Am J Cardiol 2005;96:352-7.CrossRefPubMedGoogle Scholar
  8. 8.
    Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: An intravascular ultrasound study. Circulation 2004;110:3424-9.CrossRefPubMedGoogle Scholar
  9. 9.
    Nakahara T, Dweck MR, Narula N, Pisapia D, Narula J, Strauss HW. Coronary artery calcification: From mechanism to molecular imaging. JACC Cardiovasc Imaging 2017;10:582-93.CrossRefPubMedGoogle Scholar
  10. 10.
    Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci USA 2013;110:10741-6.CrossRefPubMedGoogle Scholar
  11. 11.
    Mizukoshi M, Kubo T, Takarada S, Kitabata H, Ino Y, Tanimoto T, et al. Coronary superficial and spotty calcium deposits in culprit coronary lesions of acute coronary syndrome as determined by optical coherence tomography. Am J Cardiol 2013;112:34-40.CrossRefPubMedGoogle Scholar
  12. 12.
    Mehanna E, Bezerra HG, Prabhu D, Brandt E, Chamié D, Yamamoto H, et al. Volumetric characterization of human coronary calcification by frequency-domain optical coherence tomography. Circ J 2013;77:2334-40.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Blau M, Nagler W, Bender MA. Fluorine-18: A new isotope for bone scanning. J Nucl Med 1962;3:332-4.PubMedGoogle Scholar
  14. 14.
    New S, Aikawa E. The role of extracellular vesicles in de novo mineralization: An additional novel mechanism of cardiovascular calcification. Arterioscler Thromb Vasc Biol 2013;33:1753-8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008;3:S131-9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Irkle A, Vesey AT, Lewis DY, Skepper JN, Bird JLE, Dweck MR, et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun 2015;6:7495.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. J Nucl Med 2010;51:1826-9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-61.CrossRefPubMedGoogle Scholar
  19. 19.
    Vesey AT, Jenkins WSA, Irkle A, Moss A, Sng G, Forsythe RO, et al. 18F-fluoride and 18F-fluorodeoxyglucose positron emission tomography after transient ischemic attack or minor ischemic stroke. Circ Cardiovasc Imaging 2017;10:e004976.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hop H, de Boer SA, Reijrink M, Kamphuisen PW, de Borst MH, Pol RA, et al. 18F-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques. J Nucl Cardiol 2018. Scholar
  21. 21.
    Joshi NV, Vesey AT, Williams MC, Shah ASV, Calvert PA, Craighead FHM, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: A prospective clinical trial. Lancet 2014;383:705-13.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee JM, Bang J-I, Koo B-K, Hwang D, Park J, Zhang J, et al. Clinical relevance of (18)F-sodium fluoride positron-emission tomography in noninvasive identification of high-risk plaque in patients with coronary artery disease. Circ Cardiovasc Imaging 2017;10:e006704.CrossRefPubMedGoogle Scholar
  23. 23.
    McKenney-Drake ML, Territo PR, Salavati A, Houshmand S, Persohn S, Liang Y, et al. 18F-NaF PET imaging of early coronary artery calcification. JACC Cardiovasc Imaging 2016;6:627-8.CrossRefGoogle Scholar
  24. 24.
    Dweck MR, Jenkins WSA, Vesey AT, Pringle MAH, Chin CWL, 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;7:371-8.CrossRefPubMedGoogle Scholar
  25. 25.
    Ishiwata Y, Kaneta T, Nawata S, Hino-Shishikura A, Yoshida K, Inoue T. Quantification of temporal changes in calcium score in active atherosclerotic plaque in major vessels by 18F-sodium fluoride PET/CT. Eur J Nucl Med Mol Imaging 2017;44:1529-37.CrossRefPubMedGoogle Scholar
  26. 26.
    Shanahan CM, Cary NRB, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: Evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999;100:2168-76.CrossRefPubMedGoogle Scholar
  27. 27.
    Niskanen L, Siitonen O, Suhonen M, Uusitupa MI. Medial artery calcification predicts cardiovascular mortality in patients with NIDDM. Diabetes Care 1994;17:1252-6.CrossRefPubMedGoogle Scholar
  28. 28.
    Lehto S, Niskanen L, Suhonen M, Ronnemaa T, Laakso M. Medial artery calcification: A neglected harbinger of cardiovascular complications in non-insulin dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996;16:978-83.CrossRefPubMedGoogle Scholar
  29. 29.
    London GM. Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731-40.CrossRefPubMedGoogle Scholar
  30. 30.
    Janssen T, Bannas P, Herrmann J, Veldhoen S, Busch JD, Treszl A, et al. Association of linear 18F-sodium fluoride accumulation in femoral arteries as a measure of diffuse calcification with cardiovascular risk factors: A PET/CT study. J Nucl Cardiol 2013;20:569-77.CrossRefPubMedGoogle Scholar
  31. 31.
    Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): A randomised clinical trial. Lancet 2011;378:1547-59.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tawakol A, Singh P, Rudd JHF, Soffer J, Cai G, Vucic E, et al. Effect of Treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol 2014;63:86-8.CrossRefPubMedGoogle Scholar
  33. 33.
    Elkhawad M, Rudd JHF, Sarov-Blat L, Cai G, Wells R, Davies LC, et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging 2012;5:911-22.CrossRefPubMedGoogle Scholar
  34. 34.
    Rudd JHF, Myers KS, Bansilal S, Machac J, Rafique A, Farkouh M, et al. 18Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible. J Am Coll Cardiol 2007;50:892-6.CrossRefPubMedGoogle Scholar
  35. 35.
    van der Valk FM, Verweij SL, Zwinderman KAH, Strang AC, Kaiser Y, Marquering HA, et al. Thresholds for arterial wall inflammation quantified by 18F-FDG PET imaging: Implications for vascular interventional studies. JACC Cardiovasc Imaging 2016;9:1198-207.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Tarkin JM, Joshi FR, Rudd JHF. PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol 2014;11:443-57.CrossRefPubMedGoogle Scholar
  37. 37.
    Blomberg BA, Thomassen A, de Jong PA, Simonsen JA, Lam MGEH, Nielsen AL, et al. Impact of personal characteristics and technical factors on quantification of sodium 18F-fluoride uptake in human arteries: Prospective evaluation of healthy subjects. J Nucl Med 2015;56:1534-40.CrossRefPubMedGoogle Scholar
  38. 38.
    Blomberg B, Thomassen A, Takx RA, Vilstrup M, Hess S, Nielsen A. Delayed sodium 18F-fluoride PET/CT imaging does not improve quantification of vascular calcification metabolism: Results from the CAMONA study. J Nucl Cardiol 2013;21:293-304.CrossRefPubMedGoogle Scholar
  39. 39.
    Pawade TA, Cartlidge TRG, Jenkins WSA, Adamson PD, Robson P, Lucatelli C, et al. Optimization and reproducibility of aortic valve 18F-fluoride positron emission tomography in patients with aortic stenosis. Circ Cardiovasc Imaging 2016;9:e005131.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Dweck MR, Chow MWL, 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;59:1539-48.CrossRefPubMedGoogle Scholar
  41. 41.
    De Oliveira-Santos M, Castelo-Branco M, Silva R, Gomes A, Chichorro N, Abrunhosa A, et al. Atherosclerotic plaque metabolism in high cardiovascular risk subjects—A subclinical atherosclerosis imaging study with 18F-NaF PET–CT. Atherosclerosis 2017;260:41-6.CrossRefPubMedGoogle Scholar
  42. 42.
    Jaskowiak CJ, Bianco JA, Perlman SB, Fine JP. Influence of reconstruction iterations on 18F-FDG PET/CT standardized uptake values. J Nucl Med 2005;46:424-8.PubMedGoogle Scholar
  43. 43.
    Pannu HK, Alvarez W, Fishman EK. β-Blockers for cardiac CT: A primer for the radiologist. Am J Roentgenol 2006;186:S341-5.CrossRefGoogle Scholar
  44. 44.
    Andreucci M, Solomon R, Tasanarong A. Side effects of radiographic contrast media: Pathogenesis, risk factors, and prevention. Biomed Res Int 2014;2014:741018.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Zaidi H, Alavi A. Current trends in PET and combined (PET/CT and PET/MR) systems design. PET Clin 2007;2:109-23.CrossRefPubMedGoogle Scholar
  46. 46.
    Alavi A, Werner TJ, Høilund-Carlsen PF. What can be and what cannot be accomplished with PET to detect and characterize atherosclerotic plaques. J Nucl Cardiol 2017. (Epub ahead of print).
  47. 47.
    Soret M, Bacharach SL. Partial-volume effect in PET tumor imaging*. J Nucl Med 2007;48:932-46.CrossRefPubMedGoogle Scholar
  48. 48.
    Tarkin JM, Joshi FR, Evans NR, Chowdhury MM, Figg NL, Shah AV, et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to [18F]FDG PET imaging. J Am Coll Cardiol 2017;69:1774-91.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Rubeaux M, Joshi N, Dweck MR, Fletcher A, Motwani M, Thomson LE, et al. Demons versus Level-Set motion registration for coronary (18)F-sodium fluoride PET. Proc SPIE Int Soc Opt Eng 2016;27:9784.Google Scholar
  50. 50.
    Rubeaux M, Joshi NV, Dweck MR, Fletcher A, Motwani M, Thomson LE, et al. Motion correction of 18F-NaF PET for imaging coronary atherosclerotic plaques. J Nucl Med 2016;57:54-9.CrossRefPubMedGoogle Scholar
  51. 51.
    Cal-Gonzalez J, Li X, Heber D, Rausch I, Moore SC, Schäfers K, et al. Partial volume correction for improved PET quantification in 18F-NaF imaging of atherosclerotic plaques. J Nucl Cardiol 2017. (Epub ahead of print)
  52. 52.
    Beheshti M, Saboury B, Mehta N. Detection and global quantification of cardiovascular molecular calcification by fluoro-18-fluoride positron emission tomography/computed tomography—A novel concept. Hell J Nucl Med 2011;14:114-20.PubMedGoogle Scholar
  53. 53.
    Fiz F, Morbelli S, Bauckneht M, Piccardo A, Ferrarazzo G, Nieri A, et al. Correlation between thoracic aorta 18F-natrium fluoride uptake and cardiovascular risk retrospective study. World J Radiol 2016;8:82-9.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wasilewski J, Niedziela J, Osadnik T, Duszańska A, Sraga W, Desperak P, et al. Predominant location of coronary artery atherosclerosis in the left anterior descending artery. The impact of septal perforators and the myocardial bridging effect. Kardiochir Torakochir Pol 2015;12:379-85.Google Scholar
  55. 55.
    Han JH, Lim SY, Lee MS, Lee WW. Sodium [18F]fluoride PET/CT in myocardial infarction. Mol Imaging Biol 2015;17:214-21.CrossRefPubMedGoogle Scholar
  56. 56.
    Giovanna Trivieri M, Dweck MR, Abgral R, Robson PM, Karakatsanis NA, Lala A, et al. 18F-sodium fluoride PET/MR for the assessment of cardiac amyloidosis. J Am Coll Cardiol 2016;68:2712-4.CrossRefGoogle Scholar
  57. 57.
    Marchesseau S, Seneviratna A, Sjöholm AT, Qin DL, Ho JXM, Hausenloy DJ, et al. Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction. J Nucl Cardiol 2017. (Epub ahead of print).
  58. 58.
    Zhang Y, Safar ME, Iaria P, Lieber A, Peroz J, Protogerou AD, et al. Cardiac and arterial calcifications and all-cause mortality in the elderly: The PROTEGER Study. Atherosclerosis 2010;213:622-6.CrossRefPubMedGoogle Scholar
  59. 59.
    Rossi A, Targher G, Zoppini G, Cicoira M, Bonapace S, Negri C, et al. Aortic and mitral annular calcifications are predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes. Diabetes Care 2012;35:1781-6.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Barasch E, Gottdiener JS, Marino Larsen EK, Chaves PHM, Newman AB. Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (the cardiovascular health study). Am J Cardiol 2006;97:1281-6.CrossRefPubMedGoogle Scholar

Copyright information

© American Society of Nuclear Cardiology 2018

Authors and Affiliations

  • Jamie W. Bellinge
    • 1
    • 2
  • Roslyn J. Francis
    • 2
    • 3
  • Kamran Majeed
    • 1
    • 2
  • Gerald F. Watts
    • 1
    • 2
  • Carl J. Schultz
    • 1
    • 2
  1. 1.Department of CardiologyRoyal Perth HospitalPerthAustralia
  2. 2.School of MedicineUniversity of Western AustraliaPerthAustralia
  3. 3.Department of Nuclear MedicineSir Charles Gairdner HospitalPerthAustralia

Personalised recommendations