Cardiac amyloidosis (CA) is a progressive and life-threatening manifestation of systemic amyloidosis characterized by extracellular deposition of insoluble amyloid fibrils in the myocardium. The two most common subtypes of CA are immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloidosis, with ATTR further classified into hereditary (ATTRv) and wild-type (ATTRwt) forms. Early and accurate diagnosis of CA remains challenging, as the current gold standard, endomyocardial biopsy, is invasive and subject to sampling heterogeneity. In recent years, the rapid development of positron emission tomography (PET) molecular imaging has offered new possibilities for noninvasive detection, quantification, and monitoring of cardiac amyloid deposition. This review summarizes recent advances in PET imaging applied to CA, focusing on the performance and clinical potential of several emerging amyloid-targeting radiotracers. 11C-PiB demonstrates excellent sensitivity for detecting AL-CA but is limited by its short half-life (20 minutes) and high production costs. 18F-florbetapir, with a longer half-life of approximately 2 hours, shows promise for identifying CA and monitoring disease progression, although its ability to distinguish AL from ATTR subtypes remains suboptimal. Similarly, 18F-florbetaben and 18F-flutemetamol have been employed for cardiac amyloid imaging, with encouraging results in detecting myocardial amyloid burden, yet their specificity for amyloid subtyping requires further validation. The novel radiotracer 124I-evuzamitide (124I-p5+14) has demonstrated broad-spectrum targeting of systemic amyloid deposits and superior performance in imaging multiorgan involvement, although its prolonged half-life and associated radiation exposure may limit widespread clinical use. Future directions include the development of subtype-specific PET tracers, optimization of quantitative imaging techniques, and the integration of artificial intelligence for automated burden assessment and prognostication. Furthermore, PET imaging has the potential to serve as a biomarker for treatment response, facilitating individualized therapeutic strategies. Advances in amyloid PET imaging will undoubtedly play a crucial role in improving the diagnosis, management, and long-term prognosis of patients with cardiac amyloidosis.
References
[1]
Falk, R.H., Alexander, K.M., Liao, R. and Dorbala, S. (2016) AL (Light-Chain) Cardiac Amyloidosis. Journal of the American College of Cardiology, 68, 1323-1341. https://doi.org/10.1016/j.jacc.2016.06.053
[2]
Ruberg, F.L., Grogan, M., Hanna, M., Kelly, J.W. and Maurer, M.S. (2019) Transthyretin Amyloid Cardiomyopathy. Journal of the American College of Cardiology, 73, 2872-2891. https://doi.org/10.1016/j.jacc.2019.04.003
[3]
Razvi, Y., Porcari, A., Di Nora, C., Patel, R.K., Ioannou, A., Rauf, M.U., et al. (2023) Cardiac Transplantation in Transthyretin Amyloid Cardiomyopathy: Outcomes from Three Decades of Tertiary Center Experience. Frontiers in Cardiovascular Medicine, 9, Article 1075806. https://doi.org/10.3389/fcvm.2022.1075806
Cha, M.J., Kim, C., Park, C.H., Hong, Y.J., Shin, J.M., Kim, T.H., et al. (2022) Differential Diagnosis of Thick Myocardium According to Histologic Features Revealed by Multiparametric Cardiac Magnetic Resonance Imaging. Korean Journal of Radiology, 23, 581-597. https://doi.org/10.3348/kjr.2021.0815
[6]
Leedy, D.J., Cuddy, S.A.M. and Cheng, R.K. (2023) Transthyretin Cardiac Amyloidosis: Underrecognized in the Underrepresented. Journal of the American Heart Association, 12, e030802. https://doi.org/10.1161/jaha.123.030802
[7]
Ota, S., Izumiya, Y., Kitada, R., Nishi, T., Taruya, A., Wada, T., et al. (2023) Diagnostic Significance of Paradoxical Left Ventricular Hypertrophy in Detecting Cardiac Amyloidosis. IJC Heart & Vasculature, 49, Article ID: 101279. https://doi.org/10.1016/j.ijcha.2023.101279
[8]
Zhao, M., Calabretta, R., Yu, J., Binder, P., Hu, S., Hacker, M., et al. (2022) Nuclear Molecular Imaging of Disease Burden and Response to Treatment for Cardiac Amyloidosis. Biology, 11, Article 1395. https://doi.org/10.3390/biology11101395
[9]
Sabbour, H., Hasan, K.Y., Al Badarin, F., Alibazoglu, H., Rivard, A.L., Romany, I., et al. (2021) From Clinical Clues to Final Diagnosis: The Return of Detective Work to Clinical Medicine in Cardiac Amyloidosis. Frontiers in Cardiovascular Medicine, 8, Article 644508. https://doi.org/10.3389/fcvm.2021.644508
[10]
Quarta, C.C., Gonzalez-Lopez, E., Gilbertson, J.A., Botcher, N., Rowczenio, D., Petrie, A., et al. (2017) Diagnostic Sensitivity of Abdominal Fat Aspiration in Cardiac Amyloidosis. European Heart Journal, 38, 1905-1908. https://doi.org/10.1093/eurheartj/ehx047
[11]
Klunk, W.E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D.P., et al. (2004) Imaging Brain Amyloid in Alzheimer’s Disease with Pittsburgh Compound-B. Annals of Neurology, 55, 306-319. https://doi.org/10.1002/ana.20009
[12]
Antoni, G., Lubberink, M., Estrada, S., Axelsson, J., Carlson, K., Lindsjö, L., et al. (2012) In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET. Journal of Nuclear Medicine, 54, 213-220. https://doi.org/10.2967/jnumed.111.102053
[13]
Lee, S., Lee, E.S., Choi, H., Im, H., Koh, Y., Lee, M., et al. (2015) 11c-Pittsburgh B PET Imaging in Cardiac Amyloidosis. JACC: Cardiovascular Imaging, 8, 50-59. https://doi.org/10.1016/j.jcmg.2014.09.018
[14]
Pilebro, B., Arvidsson, S., Lindqvist, P., Sundström, T., Westermark, P., Antoni, G., et al. (2018) Positron Emission Tomography (PET) Utilizing Pittsburgh Compound B (PIB) for Detection of Amyloid Heart Deposits in Hereditary Transthyretin Amyloidosis (ATTR). Journal of Nuclear Cardiology, 25, 240-248. https://doi.org/10.1007/s12350-016-0638-5
[15]
Takasone, K., Katoh, N., Takahashi, Y., Abe, R., Ezawa, N., Yoshinaga, T., et al. (2020) Non-Invasive Detection and Differentiation of Cardiac Amyloidosis Using 99mtc-Pyrophosphate Scintigraphy and 11c-Pittsburgh Compound B PET Imaging. Amyloid, 27, 266-274. https://doi.org/10.1080/13506129.2020.1798223
[16]
Villemagne, V.L., Ong, K., Mulligan, R.S., Holl, G., Pejoska, S., Jones, G., et al. (2011) Amyloid Imaging with 18F-Florbetaben in Alzheimer Disease and Other Dementias. Journal of Nuclear Medicine, 52, 1210-1217. https://doi.org/10.2967/jnumed.111.089730
[17]
Dorbala, S. and Kijewski, M.F. (2023) Molecular Imaging of Systemic and Cardiac Amyloidosis: Recent Advances and Focus on the Future. Journal of Nuclear Medicine, 64, 20S-28S. https://doi.org/10.2967/jnumed.122.264866
[18]
Clark, C.M. (2011) Use of Florbetapir-Pet for Imaging Β-Amyloid Pathology. Journal of the American Medical Association, 305, 275-283. https://doi.org/10.1001/jama.2010.2008
[19]
Yang, L., Rieves, D. and Ganley, C. (2012) Brain Amyloid Imaging—FDA Approval of Florbetapir F18 Injection. New England Journal of Medicine, 367, 885-887. https://doi.org/10.1056/nejmp1208061
[20]
Dorbala, S., Vangala, D., Semer, J., Strader, C., Bruyere, J.R., Di Carli, M.F., et al. (2014) Imaging Cardiac Amyloidosis: A Pilot Study Using 18f-Florbetapir Positron Emission Tomography. European Journal of Nuclear Medicine and Molecular Imaging, 41, 1652-1662. https://doi.org/10.1007/s00259-014-2787-6
[21]
Park, M., Padera, R.F., Belanger, A., Dubey, S., Hwang, D.H., Veeranna, V., et al. (2015) 18F-Florbetapir Binds Specifically to Myocardial Light Chain and Transthyretin Amyloid Deposits. Circulation: Cardiovascular Imaging, 18, 478-499. https://doi.org/10.1161/circimaging.114.002954
[22]
Cuddy, S.A.M., Bravo, P.E., Falk, R.H., El-Sady, S., Kijewski, M.F., Park, M., et al. (2020) Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis. JACC: Cardiovascular Imaging, 13, 1325-1336. https://doi.org/10.1016/j.jcmg.2020.02.025
[23]
Gertz, M.A., Comenzo, R., Falk, R.H., Fermand, J.P., Hazenberg, B.P., Hawkins, P.N., et al. (2005) Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. American Journal of Hematology, 79, 319-328. https://doi.org/10.1002/ajh.20381
[24]
Ehman, E.C., El-Sady, M.S., Kijewski, M.F., Khor, Y.M., Jacob, S., Ruberg, F.L., et al. (2019) Early Detection of Multiorgan Light-Chain Amyloidosis by Whole-Body 18F-Florbetapir PET/CT. Journal of Nuclear Medicine, 60, 1234-1239. https://doi.org/10.2967/jnumed.118.221770
[25]
Clerc, O.F., Datar, Y., Cuddy, S.A.M., Bianchi, G., Taylor, A., Benz, D.C., et al. (2024) Prognostic Value of Left Ventricular 18f-Florbetapir Uptake in Systemic Light-Chain Amyloidosis. JACC: Cardiovascular Imaging, 17, 911-922. https://doi.org/10.1016/j.jcmg.2024.05.002
[26]
Law, W.P., Wang, W.Y.S., Moore, P.T., Mollee, P.N. and Ng, A.C.T. (2016) Cardiac Amyloid Imaging with 18F-Florbetaben PET: A Pilot Study. Journal of Nuclear Medicine, 57, 1733-1739. https://doi.org/10.2967/jnumed.115.169870
[27]
Baratto, L., Park, S.Y., Hatami, N., Gulaka, P., Vasanawala, S., Yohannan, T.K., et al. (2018) 18F-Florbetaben Whole-Body PET/MRI for Evaluation of Systemic Amyloid Deposition. EJNMMI Research, 8, Article No. 66. https://doi.org/10.1186/s13550-018-0425-1
[28]
Kircher, M., Ihne, S., Brumberg, J., Morbach, C., Knop, S., Kortüm, K.M., et al. (2019) Detection of Cardiac Amyloidosis with 18F-Florbetaben-PET/Ct in Comparison to Echocardiography, Cardiac MRI and DPD-Scintigraphy. European Journal of Nuclear Medicine and Molecular Imaging, 46, 1407-1416. https://doi.org/10.1007/s00259-019-04290-y
[29]
Leuzy, A., Savitcheva, I., Chiotis, K., Lilja, J., Andersen, P., Bogdanovic, N., et al. (2019) Clinical Impact of [18F] Flutemetamol PET among Memory Clinic Patients with an Unclear Diagnosis. European Journal of Nuclear Medicine and Molecular Imaging, 46, 1276-1286. https://doi.org/10.1007/s00259-019-04297-5
[30]
Dietemann, S. and Nkoulou, R. (2019) Amyloid PET Imaging in Cardiac Amyloidosis: A Pilot Study Using 18F-Flutemetamol Positron Emission Tomography. Annals of Nuclear Medicine, 33, 624-628. https://doi.org/10.1007/s12149-019-01372-7
[31]
Papathanasiou, M., Kessler, L., Carpinteiro, A., Hagenacker, T., Nensa, F., Umutlu, L., et al. (2022) 18F-Flutemetamol Positron Emission Tomography in Cardiac Amyloidosis. Journal of Nuclear Cardiology, 29, 779-789. https://doi.org/10.1007/s12350-020-02363-2
[32]
Abrahamson, E.E., Padera, R.F., Davies, J., Farrar, G., Villemagne, V.L., Dorbala, S., et al. (2022) The Flutemetamol Analogue Cyano-Flutemetamol Detects Myocardial AL and ATTR Amyloid Deposits: A Post-Mortem Histofluorescence Analysis. Amyloid, 30, 169-187. https://doi.org/10.1080/13506129.2022.2141623
[33]
Martin, E.B., Williams, A., Heidel, E., Macy, S., Kennel, S.J. and Wall, J.S. (2013) Peptide P5 Binds Both Heparinase-Sensitive Glycosaminoglycans and Fibrils in Patient-Derived AL Amyloid Extracts. Biochemical and Biophysical Research Communications, 436, 85-89. https://doi.org/10.1016/j.bbrc.2013.05.063
[34]
Wall, J., Martin, E., Richey, T., Stuckey, A., Macy, S., Wooliver, C., et al. (2015) Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis. Molecules, 20, 7657-7682. https://doi.org/10.3390/molecules20057657
[35]
Wall, J.S., Martin, E.B., Endsley, A., Stuckey, A.C., Williams, A.D., Powell, D., et al. (2021) First in Human Evaluation and Dosimetry Calculations for Peptide 124i-p5+14—A Novel Radiotracer for the Detection of Systemic Amyloidosis Using PET/CT Imaging. Molecular Imaging and Biology, 24, 479-488. https://doi.org/10.1007/s11307-021-01681-2
[36]
Clerc, O.F., Cuddy, S.A.M., Robertson, M., Vijayakumar, S., Neri, J.C., Chemburkar, V., et al. (2023) Cardiac Amyloid Quantification Using 124I-Evuzamitide (124I-p5+14) versus 18F-Florbetapir. JACC: Cardiovascular Imaging, 16, 1419-1432. https://doi.org/10.1016/j.jcmg.2023.07.007
[37]
Clerc, O.F., Vijayakumar, S. and Dorbala, S. (2024) Radionuclide Imaging of Cardiac Amyloidosis: An Update and Future Aspects. Seminars in Nuclear Medicine, 54, 717-732. https://doi.org/10.1053/j.semnuclmed.2024.05.012
[38]
Martin, E.B., Stuckey, A., Powell, D., Lands, R., Whittle, B., Wooliver, C., et al. (2023) Clinical Confirmation of Pan-Amyloid Reactivity of Radioiodinated Peptide 124i-p5+14 (AT-01) in Patients with Diverse Types of Systemic Amyloidosis Demonstrated by PET/CT Imaging. Pharmaceuticals, 16, Article 629. https://doi.org/10.3390/ph16040629
