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Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis

  • Biomarkers of Heart Failure (WH Tang & J Grodin, Section Editor)
  • Published:
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Abstract

Purpose of Review

Transthyretin amyloidosis is an increasingly recognized cause of restrictive cardiomyopathy related to amyloid fibril deposition in cardiac tissues. As treatment therapies have emerged for transthyretin amyloidosis (ATTR), so has interest in using biomarkers to identify disease prior to advanced presentation.

Recent Findings

Lower levels of transthyretin and retinol binding protein-4 have been demonstrated in patients with pathogenic mutations of transthyretin either with or without clinical disease. Levels associate with the severity of mutations as well as response to treatment with transthyretin stabilizers or small interfering RNA molecules which silence transthyretin production. Transthyretin stability is the rate limiting step of amyloid fibril formation and directly measuring transthyretin kinetic stability has the potential to identify patients as risk as well as therapeutic response to treatment regardless of pathogenic or wild-type genetics. In addition, non-antibody protein-based peptide probes have been developed that directedly measure misfolded transthyretin oligomers due to transthyretin breakdown. Although promising, both TTR kinetic and protein peptide probes remain in early stages of clinical investigation.

Summary

Transthyretin, retinol binding protein-4, transthyretin kinetic stability, and protein-based peptide probes have potential as biomarkers to facilitate an earlier ATTR diagnosis for patients with pathogenic transthyretin mutations.

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References

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

  1. Rapezzi C, Lorenzini M, Longhi S, Milandri A, Gagliardi C, Bartolomei I, et al. Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015;20(2):117–24.

    Article  CAS  PubMed  Google Scholar 

  2. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 2012;98(21):1546–54.

    Article  PubMed  Google Scholar 

  3. Kapoor M, Rossor AM, Laura M, Reilly MM. Clinical presentation, diagnosis and treatment of TTR amyloidosis. J Neuromuscul Dis. 2019;6(2):189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  5. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63–76.

    Article  CAS  PubMed  Google Scholar 

  6. Cruz MW. Tafamidis for autonomic neuropathy in hereditary transthyretin (ATTR) amyloidosis: a review. Clin Auton Res. 2019;29(Suppl 1):19–24.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16–26.

    Article  CAS  PubMed  Google Scholar 

  8. •• 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(11):1007–16. This study is a major clinical trial demonstrating the clinical efficacy of transthyretin stabilizing therapies that improve clinical outcomes.

    Article  CAS  PubMed  Google Scholar 

  9. 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(1):22–31.

    Article  CAS  PubMed  Google Scholar 

  10. Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799–806.

    Article  CAS  PubMed  Google Scholar 

  11. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68(10):1014–20.

    Article  PubMed  Google Scholar 

  12. Hanson JLS, Arvanitis M, Koch CM, Berk JL, Ruberg FL, Prokaeva T, et al. Use of serum transthyretin as a prognostic indicator and predictor of outcome in cardiac amyloid disease associated with wild-type transthyretin. Circ Heart Fail. 2018;11(2):e004000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Judge DP, Heitner SB, Falk RH, Maurer MS, Shah SJ, Witteles RM, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019;74(3):285–95.

    Article  CAS  PubMed  Google Scholar 

  14. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222–8 e1.

    Article  CAS  PubMed  Google Scholar 

  15. Ingenbleek Y, De Visscher M. Hormonal and nutritional status: critical conditions for endemic goiter epidemiology? Metabolism. 1979;28(1):9–19.

    Article  CAS  PubMed  Google Scholar 

  16. Dickson PW, Howlett GJ, Schreiber G. Metabolism of prealbumin in rats and changes induced by acute inflammation. Eur J Biochem. 1982;129(2):289–93.

    Article  CAS  PubMed  Google Scholar 

  17. Ingenbleek Y, Young V. Transthyretin (prealbumin) in health and disease: nutritional implications. Annu Rev Nutr. 1994;14:495–533.

    Article  CAS  PubMed  Google Scholar 

  18. Marcason W. Should albumin and prealbumin be used as indicators for malnutrition? J Acad Nutr Diet. 2017;117(7):1144.

    Article  PubMed  Google Scholar 

  19. Berk J CL, Hankinson E, Falzone R, Figueroa Y, Hutabarat R, Butler J, Kretschmer M, Sah D, Cehelsky J, Vaishnaw A, Gollob J. Serial measurements of circulating transthyretin (TTR) in subjects with TTR amyloidosis or carriers of mutant TTR. Meeting of the Peripheral-Nerve-Society. 2011;16.

  20. Buxbaum J, Anan I, Suhr O. Serum transthyretin levels in Swedish TTR V30M carriers. Amyloid. 2010;17(2):83–5.

    Article  CAS  PubMed  Google Scholar 

  21. Buxbaum J, Koziol J, Connors LH. Serum transthyretin levels in senile systemic amyloidosis: effects of age, gender and ethnicity. Amyloid. 2008;15(4):255–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A. 2002;99(Suppl 4):16427–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Coelho T, Chorao R, Sousa A, Alves A, Torres MF, Saraiva M. Compound heterozygotes of transthyretin Met30 and transthyretin Met119 are protected from the devastating effects of familial amyloid polyneuropathy. J Neuromusc Disord. 1996;6(S20).

  24. Hornstrup LS, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy. Arterioscler Thromb Vasc Biol. 2013;33(6):1441–7.

    Article  CAS  PubMed  Google Scholar 

  25. Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.

    Article  PubMed  PubMed Central  Google Scholar 

  26. • TS GD, De Los Santos J, Helmke S, Guadalupe S, Maurer M. Tafamidis increases serum TTR (prealbumin) levels in both ATTRh and ATTRwt cardiac amyloidosis. Journal of Cardiac Failure. 2019;25(8):S21. This study associates changes in transthyretin levels with a response to therapy outlining the potential for transthyretin to serve as a surrogate for treatment efficacy.

    Google Scholar 

  27. Noy N, Li L, Abola MV, Berger NA. Is retinol binding protein 4 a link between adiposity and cancer? Horm Mol Biol Clin Investig. 2015;23(2):39–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hyung SJ, Deroo S, Robinson CV. Retinol and retinol-binding protein stabilize transthyretin via formation of retinol transport complex. ACS Chem Biol. 2010;5(12):1137–46.

    Article  CAS  PubMed  Google Scholar 

  29. Hamilton JA, Benson MD. Transthyretin: a review from a structural perspective. Cell Mol Life Sci. 2001;58(10):1491–521.

    Article  CAS  PubMed  Google Scholar 

  30. Santos D, Coelho T, Alves-Ferreira M, Sequeiros J, Mendonca D, Alonso I, et al. Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M). Eur J Hum Genet. 2016;24(5):756–60.

    Article  CAS  PubMed  Google Scholar 

  31. • Arvanitis M, Simon S, Chan G, Fine D, Beardsley P, La Valley M, et al. Retinol binding protein 4 (RBP4) concentration identifies V122I transthyretin cardiac amyloidosis. Amyloid. 2017;24(sup1):120–1 This study serves as an excellent review of the role of retinol binding protein 4 in ATTR and the associations of retinol binding protein and clinical outcomes in ATTR.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Arvanitis M, Koch CM, Chan GG, Torres-Arancivia C, LaValley MP, Jacobson DR, et al. Identification of transthyretin cardiac amyloidosis using serum retinol-binding protein 4 and a clinical prediction model. JAMA Cardiol. 2017;2(3):305–13.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sousa A, Coelho T, Barros J, Sequeiros J. Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Povoa do Varzim and Vila do Conde (north of Portugal). Am J Med Genet. 1995;60(6):512–21.

    Article  CAS  PubMed  Google Scholar 

  34. Rappley I, Monteiro C, Novais M, Baranczak A, Solis G, Wiseman RL, et al. Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry. 2014;53(12):1993–2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schonhoft JD, Monteiro C, Plate L, Eisele YS, Kelly JM, Boland D, et al. Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients. Sci Transl Med. 2017;9(407).

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Nicholas S. Hendren, Lori R. Roth & Justin L. Grodin

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  1. Nicholas S. Hendren
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  2. Lori R. Roth
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Correspondence to Justin L. Grodin.

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Conflict of Interest

Dr. Grodin received research funding from the Texas Health Resources Clinical Scholarship and receives consulting income from Pfizer and Eidos Therapeutics. Dr. Nicholas Hendren and Lori Roth declare that they have no conflict of interest.

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Hendren, N.S., Roth, L.R. & Grodin, J.L. Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis. Curr Heart Fail Rep 17, 77–83 (2020). https://doi.org/10.1007/s11897-020-00457-z

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