Targeted Nuclear Imaging Probes for Cardiac Amyloidosis

Nuclear Cardiology (V Dilsizian, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nuclear Cardiology


Purpose of Review

The aim of the present manuscript is to review the latest advancements of radionuclide molecular imaging in the diagnosis and prognosis of individuals with cardiac amyloidosis.

Recent Findings

99mTechnetium labeled bone tracer scintigraphy had been known to image cardiac amyloidosis, since the 1980s; over the past decade, bone scintigraphy has been revived specifically to diagnose transthyretin cardiac amyloidosis. 18F labeled and 11C labeled amyloid binding radiotracers developed for imaging Alzheimer’s disease, have been repurposed since 2013, to image light chain and transthyretin cardiac amyloidosis.


99mTechnetium bone scintigraphy for transthyretin cardiac amyloidosis, and amyloid binding targeted PET imaging for light chain and transthyretin cardiac amyloidosis, are emerging as highly accurate methods. Targeted radionuclide imaging may soon replace endomyocardial biopsy in the evaluation of patients with suspected cardiac amyloidosis. Further research is warranted on the role of targeted imaging to quantify cardiac amyloidosis and to guide therapy.


Amyloidosis Radionuclide imaging Molecular imaging Transthyretin amyloidosis Light chain amyloidosis Diagnosis Prognosis 



This work was supported in part by a grant from the National Institutes of Health (1T32HL094301, Dr. Bravo) and (1RO1-1R01HL130563, Dr. Dorbala).

Compliance with Ethical Standards

Conflict of Interest

Paco E. Bravo declares that he has no conflict of interest.

Sharmila Dorbala has received grants from the National Institutes of Health (RO1 HL 130563) and the American Heart Association (16 CSA 28880004), and grants from Astellas Pharma.

Human and Animal Rights and Informed Consent

This article does not contain any previously unpublished studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32(1):45–59.PubMedGoogle Scholar
  2. 2.
    Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361–71.CrossRefPubMedGoogle Scholar
  3. 3.
    Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22(18):3751–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005;165(12):1425–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Delahaye N, Dinanian S, Slama MS, Mzabi H, Samuel D, Adams D, et al. Cardiac sympathetic denervation in familial amyloid polyneuropathy assessed by iodine-123 metaiodobenzylguanidine scintigraphy and heart rate variability. Eur J Nucl Med. 1999;26(4):416–24.CrossRefPubMedGoogle Scholar
  6. 6.
    Algalarrondo V, Antonini T, Theaudin M, Chemla D, Benmalek A, Lacroix C, et al. Cardiac Dysautonomia predicts long-term survival in hereditary transthyretin amyloidosis after liver transplantation. JACC Cardiovasc Imaging. 2016;9(12):1432–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Coutinho MC, Cortez-Dias N, Cantinho G, Conceicao I, Oliveira A, Bordalo e Sa A, et al. Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy. Circ Cardiovasc Imaging. 2013;6(5):627–36.CrossRefPubMedGoogle Scholar
  8. 8.
    Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005;46(6):1076–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, et al. Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis. JAMA Cardiol. 2016;1(8):880–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging. 2014;15(11):1289–98.CrossRefPubMedGoogle Scholar
  11. 11.
    • Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. 2013;6(2):195–201. This publication has identified a threshold heart to contralateral lung ratio of > 1.6 as highly specific and sensitive to identify ATTR cardiac amyloidosis. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    • Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404–12. This is the largest experience to date compiling data from multiple centers and showing the high accuracy of bone imaging in the diagnosis of ATTR cardiac amyloidosis. CrossRefPubMedGoogle Scholar
  13. 13.
    Bonte FJ, Parkey RW, Graham KD, Moore J, Stokely EM. A new method for radionuclide imaging of myocardial infarcts. Radiology. 1974;110(2):473–4.CrossRefPubMedGoogle Scholar
  14. 14.
    Buja LM, Parkey RW, Stokely EM, Bonte FJ, Willerson JT. Pathophysiology of technetium-99m stannous pyrophosphate and thallium-201 scintigraphy of acute anterior myocardial infarcts in dogs. J Clin Invest. 1976;57(6):1508–22.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dewanjee MK, Kahn PC. Mechanism of localization of 99mTc-labeled pyrophosphate and tetracycline in infarcted myocardium. J Nucl Med. 1976;17(7):639–46.PubMedGoogle Scholar
  16. 16.
    Pepys MB, Dyck RF, de Beer FC, Skinner M, Cohen AS. Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin Exp Immunol. 1979;38(2):284–93.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Stats MA, Stone JR. Varying levels of small microcalcifications and macrophages in ATTR and AL cardiac amyloidosis: implications for utilizing nuclear medicine studies to subtype amyloidosis. Cardiovasc Pathol. 2016;25(5):413–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Yamada T, Tamaki N, Morishima S, Konishi J, Yoshida A, Matsumori A. Time course of myocardial infarction evaluated by indium-111-antimyosin monoclonal antibody scintigraphy: clinical implications and prognostic value. J Nucl Med. 1992;33(8):1501–8.PubMedGoogle Scholar
  19. 19.
    Margari ZJ, Anastasiou-Nana MI, Terrovitis J, Toumanidis S, Agapitos EV, Lekakis JP, et al. Indium-111 monoclonal antimyosin cardiac scintigraphy in suspected acute myocarditis: evolution and diagnostic impact. Int J Cardiol. 2003;90(2–3):239–45.CrossRefPubMedGoogle Scholar
  20. 20.
    Nanas JN, Margari ZJ, Lekakis JP, Alexopoulos GE, Prassopoulos V, Agapitos EV, et al. Indium-111 monoclonal antimyosin cardiac scintigraphy in men with idiopathic dilated cardiomyopathy. Am J Cardiol. 2000;85(2):214–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Valdes Olmos RA, Carrio I, Hoefnagel CA, Estorch M, ten Bokkel Huinink WW, Lopez-Pousa J, et al. High sensitivity of radiolabelled antimyosin scintigraphy in assessing anthracycline related early myocyte damage preceding cardiac dysfunction. Nucl Med Commun. 2002;23(9):871–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Unlu M, Temiz NH, Cengel A. Myocardial indium-111-antimyosin uptake in essential hypertension. Nuklearmedizin. 2003;42(3):99–103.PubMedGoogle Scholar
  23. 23.
    Nishimura T, Sada M, Sasaki H, Yutani C, Hayashi M, Amemiya H, et al. Identification of cardiac rejection in heterotopic heart transplantation using 111In-antimyosin. Eur J Nucl Med. 1987;13(7):343–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Lekakis J, Dimopoulos M, Nanas J, Prassopoulos V, Agapitos N, Alexopoulos G, et al. Antimyosin scintigraphy for detection of cardiac amyloidosis. Am J Cardiol. 1997;80(7):963–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Hobbs JR, Morgan AD. Fluorescence microscopy with Thioflavine-T in the diagnosis of amyloid. J Pathol Bacteriol. 1963;86:437–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Klunk WE, Wang Y, Huang GF, Debnath ML, Holt DP, Mathis CA. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci. 2001;69(13):1471–84.CrossRefPubMedGoogle Scholar
  27. 27.
    Biancalana M, Koide S. Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta. 2010;1804(7):1405–12.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Khurana R, Coleman C, Ionescu-Zanetti C, Carter SA, Krishna V, Grover RK, et al. Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol. 2005;151(3):229–38.CrossRefPubMedGoogle Scholar
  29. 29.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.CrossRefPubMedGoogle Scholar
  30. 30.
    • Law WP, Wang WY, Moore PT, Mollee PN, Ng AC. Cardiac amyloid imaging with 18F-Florbetaben PET: a pilot study. J Nucl Med. 2016;57(11):1733–9. This was the first publication showing the value of 18F-florbetaben to image cardiac amyloidosis. CrossRefPubMedGoogle Scholar
  31. 31.
    Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011;305(3):275–83.CrossRefPubMedGoogle Scholar
  32. 32.
    • Dorbala S, Vangala D, Semer J, Strader C, Bruyere JR Jr, Di Carli MF, et al. Imaging cardiac amyloidosis: a pilot study using (1)(8)F-florbetapir positron emission tomography. Eur J Nucl Med Mol Imaging. 2014;41(9):1652–62. This was the first publication to show the value of 18F-florbetapir to image cardiac amyloidosis. CrossRefPubMedGoogle Scholar
  33. 33.
    • Park MA, Padera RF, Belanger A, Dubey S, Hwang DH, Veeranna V, et al. 18F–Florbetapir Binds Specifically to Myocardial Light Chain and Transthyretin Amyloid Deposits: Autoradiography Study. Circ Cardiovasc Imaging. 2015;8(8). This was the first publication to demonstrate specific binding of 18F-florbetapir to myocardial AL and ATTR deposits. Google Scholar
  34. 34.
    Osborne DR, Acuff SN, Stuckey A, Wall JS. A routine PET/CT protocol with streamlined calculations for assessing cardiac amyloidosis using (18)F-Florbetapir. Front Cardiovasc Med. 2015;2:23.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    • Antoni G, Lubberink M, Estrada S, Axelsson J, Carlson K, Lindsjo L, et al. In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET. J Nucl Med. 2013;54(2):213–20. This was the first publication showing the value of 11C-PIB to image cardiac amyloidosis. CrossRefPubMedGoogle Scholar
  36. 36.
    •• Lee SP, Lee ES, Choi H, Im HJ, Koh Y, Lee MH, et al. 11C-Pittsburgh B PET imaging in cardiac amyloidosis. JACC Cardiovasc Imaging. 2015;8(1):50–9. This was the first publication showing differences in 11C-PIB uptake among patients with and without prior chemotherapy. CrossRefPubMedGoogle Scholar
  37. 37.
    Dorbala S, Kijewski MF, Park MA. Quantitative molecular imaging of cardiac amyloidosis: the journey has begun. J Nucl Cardiol. 2016;23(4):751–3.CrossRefPubMedGoogle Scholar
  38. 38.
    Bianchi C, Donadio C, Tramonti G, Lorusso P, Bellitto L, Lunghi F. 99mTc-aprotinin: a new tracer for kidney morphology and function. Eur J Nucl Med. 1984;9(6):257–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Matsumoto A, Enomoto T, Fujiwara Y, Baba H, Matsumoto R. Enhanced aggregation of beta-amyloid-containing peptides by extracellular matrix and their degradation by the 68 kDa serine protease prepared from human brain. Neurosci Lett. 1996;220(3):159–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Frautschy SA, Horn DL, Sigel JJ, Harris-White ME, Mendoza JJ, Yang F, et al. Protease inhibitor coinfusion with amyloid beta-protein results in enhanced deposition and toxicity in rat brain. J Neurosci. 1998;18(20):8311–21.PubMedGoogle Scholar
  41. 41.
    Schaadt BK, Hendel HW, Gimsing P, Jonsson V, Pedersen H, Hesse B. 99mTc-aprotinin scintigraphy in amyloidosis. J Nucl Med. 2003;44(2):177–83.PubMedGoogle Scholar
  42. 42.
    Han S, Chong V, Murray T, McDonagh T, Hunter J, Poon FW, et al. Preliminary experience of 99mTc-Aprotinin scintigraphy in amyloidosis. Eur J Haematol. 2007;79(6):494–500.CrossRefPubMedGoogle Scholar
  43. 43.
    Minamimoto R, Kubota K, Ishii K, Morooka M, Okasaki M, Miyata Y, et al. Re-evaluating the potentials and limitations of (99m)Tc-aprotinin scintigraphy for amyloid imaging. Am J Nucl Med Mol Imaging. 2013;3(3):261–71.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kozak RW, Golker CF, Stadler P. Transmissible spongiform encephalopathies (TSE): minimizing the risk of transmission by biological/biopharmaceutical products: an industry perspective. Dev Biol Stand. 1996;88:257–64.PubMedGoogle Scholar
  45. 45.
    Pepys MB, Baltz ML, de Beer FC, Dyck RF, Holford S, Breathnach SM, et al. Biology of serum amyloid P component. Ann N Y Acad Sci. 1982;389:286–98.CrossRefPubMedGoogle Scholar
  46. 46.
    Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med. 2015;373(12):1106–14.CrossRefPubMedGoogle Scholar
  47. 47.
    Hawkins PN, Myers MJ, Lavender JP, Pepys MB. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component. Lancet. 1988;1(8600):1413–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med. 1990;323(8):508–13.CrossRefPubMedGoogle Scholar
  49. 49.
    Rydh A, Suhr O, Hietala SO, Ahlstrom KR, Pepys MB, Hawkins PN. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation. Eur J Nucl Med. 1998;25(7):709–13.CrossRefPubMedGoogle Scholar
  50. 50.
    Solomon A, Weiss DT, Wall JS. Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4. Clin Cancer Res. 2003;9(10 Pt 2):3831S–8S.PubMedGoogle Scholar
  51. 51.
    Wall JS, Kennel SJ, Paulus M, Gregor J, Richey T, Avenell J, et al. Radioimaging of light chain amyloid with a fibril-reactive monoclonal antibody. J Nucl Med. 2006;47(12):2016–24.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Wall JS, Kennel SJ, Stuckey AC, Long MJ, Townsend DW, Smith GT, et al. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis. Blood. 2010;116(13):2241–4.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, the Noninvasive Cardiovascular Imaging Program, Departments of Medicine (Cardiology) and Radiology, Cardiac Amyloidosis Program, Department of MedicineBrigham and Women’s HospitalBostonUSA

Personalised recommendations