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Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation

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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

To determine the capability of 99mTc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients.

Methods

Eleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99mTc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years.

Results

Six patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99mTc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period.

Conclusions

99mTc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99mTc-DPD scan predicts cardiac symptoms onset.

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Abbreviations

TTR:

Transthyretin

IVS:

Interventricular septum

Hattr:

Hereditary transthyretin-related amyloidosis

FAP:

Familial amyloid polyneuropathy

FAC:

Familial amyloidotic cardiomyopathy

DPD:

3,3-diphosphono-1, 2-propanodicarboxylic acid

NT-proBNP:

N-terminal pro-B-type natriuretic peptide

PYP:

Pirophosphate

ECG:

Electrocardiogram

EF:

Ejection fraction

References

  1. Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: An Italian perspective. Eur Heart J 2013;34:520-8.

    Article  CAS  Google Scholar 

  2. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8:31.

    Article  Google Scholar 

  3. Glaudemans AW, van Rheenen RW, van den Berg MP, Noordzij W, Koole M, Blokzijl H, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid 2014;21:35-44.

    Article  CAS  Google Scholar 

  4. Castaño A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: Emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 2015;20:163-78.

    Article  CAS  Google Scholar 

  5. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007-16.

    Article  CAS  Google Scholar 

  6. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379:22-31.

    Article  CAS  Google Scholar 

  7. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379:11-21.

    Article  CAS  Google Scholar 

  8. Arbustini E, Merlini G. Early identification of transthyretin-related hereditary cardiac amyloidosis. JACC Cardiovasc Imaging 2014;7:511-4.

    Article  Google Scholar 

  9. Castano A, De Luca A, Weinberg R, Pozniakoff T, Blaner WS, Pirmohamed A, et al. Serial scanning with technetium pyrophosphate (99mTc-PYP) in advanced ATTR cardiac amyloidosis. J Nucl Cardiol 2016;23:1355-63.

    Article  Google Scholar 

  10. Di Bella G, Pizzino F, Minutoli F, Zito C, Donato R, Dattilo G, et al. The mosaic of the cardiac amyloidosis diagnosis: role of imaging in subtypes and stages of the disease. Eur Heart J Cardiovasc Imaging 2014;15:1307-15.

    Article  Google Scholar 

  11. Kristen AV, Scherer K, Buss S, aus dem Siepen F, Haufe S, Bauer R, et al. Noninvasive risk stratification of patients with transthyretin amyloidosis. JACC Cardiovasc Imaging 2014;7:502-10.

    Article  Google Scholar 

  12. Rapezzi C, Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone O, et al. Usefulness and limitations of acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38:470-8.

    Article  Google Scholar 

  13. Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging 2011;4:659-70.

    Article  Google Scholar 

  14. Minutoli F, Di Bella G, Sindoni A, Vita G, Baldari S. Effectiveness of skeletal scintigraphy in transthyretin-related amyloidosis. Int J Cardiol 2013;168:4988-9.

    Article  Google Scholar 

  15. Minutoli F, Di Bella G, Mazzeo A, Donato R, Russo M, Scribano E, et al. Comparison between (99m)Tc-diphosphonate imaging and MRI with late gadolinium enhancement in evaluating cardiac involvement in patients with transthyretin familial amyloid polyneuropathy. AJR Am J Roentgenol 2013;200:W256-65.

    Article  Google Scholar 

  16. Russo M, Mazzeo A, Stancanelli C, Di Leo R, Gentile L, Di Bella G, et al. Transthyretin-related familial amyloidotic polyneuropathy: Description of a cohort of patients with Leu64 mutation and late onset. J Peripher Nerv Syst 2012;17:385-90.

    Article  CAS  Google Scholar 

  17. 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;15:1289-98.

    Article  Google Scholar 

  18. Kristen AV, Haufe S, Schonland SO, Hegenbart U, Schnabel PA, Röcken C, et al. Skeletal scintigraphy indicates disease severity of cardiac involvement in patients with senile systemic amyloidosis. Int J Cardiol 2013;164:179-84.

    Article  Google Scholar 

  19. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404-12.

    Article  CAS  Google Scholar 

  20. Minutoli F, Di Bella G, Vita G, Laudicella R, Bogaert J, Baldari S. Non invasive cardiac imaging in patients with systemic amyloidosis: A practical approach with emphasis on clinical contribution of bone-seeking radiotracers. Clinical and Translational Imaging 2017;5:545-59.

    Article  Google Scholar 

  21. Mazzeo A, Russo M, Di Bella G, Minutoli F, Stancanelli C, Gentile L, et al. Transthyretin-related familial amyloid polyneuropathy (TTR-FAP): A single-center experience in sicily, an Italian endemic area. J Neuromuscul Dis 2015;2:S39-48.

    Article  Google Scholar 

  22. Gertz M, Merlini G. Definition of organ involvement and response to treatment in AL amyloidosis: An updated consensus opinion (abstr CP B). Amyloid 2010;17(Suppl 1):48-9.

    Google Scholar 

  23. Graceffa A, Russo M, Vita GL, Toscano A, Dattola R, Messina C, et al. Psychosocial impact of presymptomatic genetic testing for transthyretin amyloidotic polyneuropathy. Neuromuscul Disord 2009;19:44-8.

    Article  Google Scholar 

  24. Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD. Updates in cardiac amyloidosis: A review. J Am Heart Assoc 2012;1:e000364.

    Article  Google Scholar 

  25. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67.

    Article  CAS  Google Scholar 

  26. 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;46:1076-84.

    Article  Google Scholar 

  27. Puille M, Altland K, Linke RP, Steen-Muller MK, Kiett R, Steiner D, et al. 99mTc-DPD scintigraphy in transthyretin-related familial amyloidotic polyneuropathy. Eur J Nucl Med Mol Imaging 2002;29:376-9.

    Article  CAS  Google Scholar 

  28. Di Bella G, Minutoli F, Piaggi P, Casale M, Mazzeo A, Zito C, et al. Usefulness of combining electrocardiographic and echocardiographic findings and brain natriuretic peptide in early detection of cardiac amyloidosis in subjects with transthyretin gene mutation. Am J Cardiol 2015;116:1122-7.

    Article  CAS  Google Scholar 

  29. Vita G, Vita GL, Stancanelli C, Gentile L, Russo M, Mazzeo A. Genetic neuromuscular disorders: living the era of a therapeutic revolution. Part 1: Peripheral neuropathies. Neurol Sci 2019;40:661-9.

    Article  Google Scholar 

  30. Galat A, Van der Gucht A, Guellich A, Bodez D, Cottereau AS, Geundouz S, et al. Early phase 99mTc-HMDP scintigrapgy for the diagnosis and typing of cardiac amyloidosis. JACC Cardiovasc Imaging 2017;10:601-3.

    Article  Google Scholar 

  31. Hutt DF, Fontana M, Burniston M, Quigley AM, Petrie A, Ross JC, et al. Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid. Eur Heart J Cardiovasc Imaging. 2017;18:1344-50.

    Article  Google Scholar 

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Acknowledgements

None.

Disclosure

Minutoli F, Di Bella G, Mazzeo A, Laudicella R, Gentile L, Russo M and Baldari S have nothing to disclose and they have no relevant or material financial interests that can relate to the research described in this paper. Vita G. discloses having been on advisory board for Alnylam Therap., Akcea Therap, and Pfizer. He is also principal investigator in clinical trials sponsored by Alnylam Therap and Ionis Therap.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, University Hospital “G. Martino”, Via Consolare Valeria 1, 98125, Messina, Italy

    F. Minutoli MD, R. Laudicella MD & S. Baldari MD

  2. Department of Clinical and Experimental Medicine, University of Messina, University Hospital “G. Martino”, Via Consolare Valeria 1, 98125, Messina, Italy

    G. Di Bella MD, A. Mazzeo MD, L. Gentile MD & G. Vita MD

  3. Nemo Sud Clinical Centre, University Hospital “G. Martino”, Messina, Italy

    M. Russo MD

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  1. F. Minutoli MD
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Correspondence to R. Laudicella MD.

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Funding

Minutoli F, Di Bella G, Mazzeo A, Laudicella R, Gentile L, Russo M, Vita G and Baldari S declare that they did not receive any financial support for this study.

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Minutoli, F., Di Bella, G., Mazzeo, A. et al. Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation. J. Nucl. Cardiol. 28, 1949–1957 (2021). https://doi.org/10.1007/s12350-019-01950-2

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