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Impact of Genetic Testing in Transthyretin (ATTR) Cardiac Amyloidosis

  • Biomarkers of Heart Failure (J. Grodin & W.H.W. Tang, Section Editors)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The review’s main focus centers on the genetics of hereditary cardiac amyloidosis, highlighting the opportunities and challenges posed by the widespread availability of genetic screening and diagnostic cardiac imaging.

Recent Findings

Advancements in cardiac imaging, heightened awareness of the ATTR amyloidosis diagnosis, and greater access to genetic testing have all led to an increased appreciation of the prevalence of ATTR cardiac amyloidosis. Elucidation of the TTR molecular structure and effect of mutations on TTR function have allowed for novel TTR therapy development leading to clinical implementation of transthyretin stabilizers and transthyretin gene silencers.

Summary

The transthyretin amyloidoses are a diverse group of protein misfolding disorders with cardiac and peripheral/autonomic nervous system manifestations due to protein deposition. Genetic screening allows for the early identification of asymptomatic TTR mutation carriers. With the advent of TTR-specific therapeutics, clinical guidance is necessary for the management of individuals with mutations in the TTR gene without evidence of disease.

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References

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

  1. • Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, MJM S, Sekijima Y, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2018;25(4):215–9 An important paper published in 2018 by the International Society of Amyloidosis nomenclature committee regarding updates and consensus recommendations for nomenclature regarding the various types amyloidosis.

    CAS  PubMed  Google Scholar 

  2. Libbey CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med. 1983;143(8):1549–52.

    CAS  PubMed  Google Scholar 

  3. Robbins J. Thyroxine-binding proteins. Prog Clin Biol Res. 1976;5:331–55.

    CAS  PubMed  Google Scholar 

  4. Hou X, Aguilar MI, Small DH. Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration. FEBS J. 2007;274(7):1637–50.

    CAS  PubMed  Google Scholar 

  5. •• Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36(4):411–23 A seminal paper reviewing the molecular and clinical features of ATTR variant disease and neuropathy.

    CAS  PubMed  Google Scholar 

  6. Aus dem Siepen F, Hein S, Prestel S, Baumgartner C, Schonland S, Hegenbart U, Rocken C, Katus HA, Kristen AV. Carpal tunnel syndrome and spinal canal stenosis: harbingers of transthyretin amyloid cardiomyopathy? Clin Res Cardiol. 2019 April 5. https://doi.org/10.1007/s00392-019-01467-1.

  7. Geller HI, Singh A, Alexander KM, Mirto TM, Falk RH. Association between ruptured distal biceps tendon and wild-type transthyretin cardiac amyloidosis. Jama. 2017;318(10):962–3.

    PubMed  PubMed Central  Google Scholar 

  8. Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005;62(7):1057–62.

    PubMed  Google Scholar 

  9. Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA, et al. Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014;344(1–2):121–8.

    CAS  PubMed  Google Scholar 

  10. Gonzalez-Duarte A. Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis). Clin Auton Res. 2019;29(2):245–51.

    PubMed  Google Scholar 

  11. Vita G, Mazzeo A, Di Leo R, Ferlini A. Recurrent syncope as persistently isolated feature of transthyretin amyloidotic polyneuropathy. Neuromuscul Disord. 2005;15(3):259–61.

    PubMed  Google Scholar 

  12. Uehara T, Kakuda K, Sumi-Akamaru H, Yamauchi A, Mochizuki H, Naka T. An autopsy case of leptomeningeal amyloidosis associated with transthyretin Gly47Arg mutation. Rinsho Shinkeigaku. 2016;56(11):777–80.

    PubMed  Google Scholar 

  13. Vidal R, Garzuly F, Budka H, Lalowski M, Linke RP, Brittig F, et al. Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G). Am J Pathol. 1996;148(2):361–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. McColgan P, Viegas S, Gandhi S, Bull K, Tudor R, Sheikh F, et al. Oculoleptomeningeal amyloidosis associated with transthyretin Leu12Pro in an African patient. J Neurol. 2015;262(1):228–34.

    CAS  PubMed  Google Scholar 

  15. Petersen RB, Goren H, Cohen M, Richardson SL, Tresser N, Lynn A, et al. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol. 1997;41(3):307–13.

    CAS  PubMed  Google Scholar 

  16. Blevins G, Macaulay R, Harder S, Fladeland D, Yamashita T, Yazaki M, et al. Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His. Neurology. 2003;60(10):1625–30.

    CAS  PubMed  Google Scholar 

  17. Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003;10(3):160–84.

    CAS  PubMed  Google Scholar 

  18. Yazaki M, Connors LH, Eagle RC Jr, Leff SR, Skinner M, Benson MD. Transthyretin amyloidosis associated with a novel variant (Trp41Leu) presenting with vitreous opacities. Amyloid. 2002;9(4):263–7.

    PubMed  Google Scholar 

  19. Lobato L, Beirao I, Silva M, Fonseca I, Queiros J, Rocha G, et al. End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation, survival and prognostic factors. Amyloid. 2004;11(1):27–37.

    PubMed  Google Scholar 

  20. Duca F, Kammerlander AA, Panzenbock A, Binder C, Aschauer S, Loewe C, et al. Cardiac magnetic resonance T1 mapping in cardiac amyloidosis. J Am Coll Cardiol Img. 2018;11(12):1924–6.

    Google Scholar 

  21. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005;111(2):186–93.

    PubMed  Google Scholar 

  22. Bellavia D, Abraham TP, Pellikka PA, Al-Zahrani GB, Dispenzieri A, Oh JK, et al. Detection of left ventricular systolic dysfunction in cardiac amyloidosis with strain rate echocardiography. J Am Soc Echocardiogr. 2007;20(10):1194–202.

    PubMed  Google Scholar 

  23. Schiano-Lomoriello V, Galderisi M, Mele D, Esposito R, Cerciello G, Buonauro A, et al. Longitudinal strain of left ventricular basal segments and E/e’ ratio differentiate primary cardiac amyloidosis at presentation from hypertensive hypertrophy: an automated function imaging study. Echocardiography. 2016;33(9):1335–43.

    PubMed  Google Scholar 

  24. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49(1):9–13.

    CAS  PubMed  Google Scholar 

  25. Mints YY, Doros G, Berk JL, Connors LH, Ruberg FL. Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience. ESC Heart Fail. 2018;5(5):772–9.

    PubMed  PubMed Central  Google Scholar 

  26. Dubrey S, Pollak A, Skinner M, Falk RH. Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation. Br Heart J. 1995;74(5):541–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Feng D, Edwards WD, Oh JK, Chandrasekaran K, Grogan M, Martinez MW, et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation. 2007;116(21):2420–6.

    PubMed  Google Scholar 

  28. Barbhaiya CR, Kumar S, Baldinger SH, Michaud GF, Stevenson WG, Falk R, et al. Electrophysiologic assessment of conduction abnormalities and atrial arrhythmias associated with amyloid cardiomyopathy. Heart Rhythm. 2016;13(2):383–90.

    PubMed  Google Scholar 

  29. Anzai N, Akiyama K, Tsuchida K, Yamada M, Kito S, Yamamura Y. Treatment by pacemaker in familial amyloid polyneuropathy. Chest. 1989;96(1):80–4.

    CAS  PubMed  Google Scholar 

  30. Milner J, Teixeira RN, Marinho AV, Silva N, Calretas S, Ferrao J, Furtado E, Telo MJ, Ventura M, Cristovao J, Elvas L, Pego GM, Antonia N. Pacemaker implantation in familial amyloid polyneuropathy: when and for whom? J Interv Card Electrophysiol. 2019;55(2):207–211.

    PubMed  Google Scholar 

  31. Hamon D, Algalarrondo V, Gandjbakhch E, Extramiana F, Marijon E, Elbaz N, et al. Outcome and incidence of appropriate implantable cardioverter-defibrillator therapy in patients with cardiac amyloidosis. Int J Cardiol. 2016;222:562–8.

    PubMed  Google Scholar 

  32. Maleszewski JJ. Cardiac amyloidosis: pathology, nomenclature, and typing. Cardiovasc Pathol. 2015;24(6):343–50.

    CAS  PubMed  Google Scholar 

  33. Lehmonen L, Kaasalainen T, Atula S, Mustonen T, Holmstrom M. Myocardial tissue characterization in patients with hereditary gelsolin (AGel) amyloidosis using novel cardiovascular magnetic resonance techniques. Int J Cardiovasc Imaging. 2019;35(2):351–8.

    PubMed  PubMed Central  Google Scholar 

  34. 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.

    PubMed  Google Scholar 

  35. 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(3):376–9.

    CAS  PubMed  Google Scholar 

  36. •• 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 is the first article depicting the use of Tc-pyrophosphate scanning specifically for differentiating between light-chain and ATTR cardiac amyloidosis with incorporation of the heart-to-contralateral ratio.

    PubMed  PubMed Central  Google Scholar 

  37. 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.

    CAS  PubMed  Google Scholar 

  38. Treglia G, Glaudemans A, Bertagna F, Hazenberg BPC, Erba PA, Giubbini R, et al. Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis. Eur J Nucl Med Mol Imaging. 2018;45(11):1945–55.

    CAS  PubMed  Google Scholar 

  39. •• Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016;387(10038):2641–54 This is a very comprehensive and up-to-date-review of systemic amyloidosis and the various clinical treatments and outcomes associated with each type of amyloidosis.

    CAS  PubMed  Google Scholar 

  40. •• Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872–91 A very recent review of ATTR cardiac amyloidosis reviewing pathophysiology, diagnosis, management, and clinical treatment algorithms for ATTR disease.

    CAS  PubMed  Google Scholar 

  41. Westermark P, Sletten K, Johansson B, Cornwell GG 3rd. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A. 1990;87(7):2843–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Almeida MR, Hesse A, Steinmetz A, Maisch B, Altland K, Linke RP, et al. Transthyretin Leu 68 in a form of cardiac amyloidosis. Basic Res Cardiol. 1991;86(6):567–71.

    CAS  PubMed  Google Scholar 

  43. • Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017;19(7):733–42 A comprehensive assessment of ATTRV122I cardiac amyloidosis disussing the available data on genetic penetrance, prevalence, and outcomes seen in this specific and most frequent ATTR genetic mutation seen in the United States.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ranlov I, Alves IL, Ranlov PJ, Husby G, Costa PP, Saraiva MJ. A Danish kindred with familial amyloid cardiomyopathy revisited: identification of a mutant transthyretin-methionine111 variant in serum from patients and carriers. Am J Med. 1992;93(1):3–8.

    CAS  PubMed  Google Scholar 

  45. Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012;33(9):1120–7.

    CAS  PubMed  Google Scholar 

  46. • Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161–72 Utilizing an international registry of ATTR amyloidosis, this study describes the genotype and phenotype of ATTR cardiomyopathy in the US with comparison to the rest of the world.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Connors LH, Prokaeva T, Lim A, Theberge R, Falk RH, Doros G, et al. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607–14.

    CAS  PubMed  Google Scholar 

  48. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015;22(3):171–4.

    CAS  PubMed  Google Scholar 

  49. Hellman U, Alarcon F, Lundgren HE, Suhr OB, Bonaiti-Pellie C, Plante-Bordeneuve V. Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population. Amyloid. 2008;15(3):181–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rapezzi C, Quarta CC, Riva L, Longhi S, Gallelli I, Lorenzini M, et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol. 2010;7(7):398–408.

    CAS  PubMed  Google Scholar 

  51. Plante-Bordeneuve V, Carayol J, Ferreira A, Adams D, Clerget-Darpoux F, Misrahi M, et al. Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. J Med Genet. 2003;40(11):e120.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ikeda S, Nakazato M, Ando Y, Sobue G. Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. Neurology. 2002;58(7):1001–7.

    CAS  PubMed  Google Scholar 

  53. Misu K, Hattori N, Nagamatsu M, Ikeda S, Ando Y, Nakazato M, et al. Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features. Brain. 1999;122(Pt 10):1951–62.

    PubMed  Google Scholar 

  54. Rapezzi C, Riva L, Quarta CC, Perugini E, Salvi F, Longhi S, et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid. 2008;15(1):40–8.

    CAS  PubMed  Google Scholar 

  55. Olsson M, Hellman U, Plante-Bordeneuve V, Jonasson J, Lang K, Suhr OB. Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients. Clin Genet. 2009;75(2):163–8.

    CAS  PubMed  Google Scholar 

  56. Ihse E, Ybo A, Suhr O, Lindqvist P, Backman C, Westermark P. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J Pathol. 2008;216(2):253–61.

    CAS  PubMed  Google Scholar 

  57. Ihse E, Rapezzi C, Merlini G, Benson MD, Ando Y, Suhr OB, et al. Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis. Amyloid. 2013;20(3):142–50.

    CAS  PubMed  Google Scholar 

  58. Bergstrom J, Gustavsson A, Hellman U, Sletten K, Murphy CL, Weiss DT, et al. Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology. J Pathol. 2005;206(2):224–32.

    PubMed  Google Scholar 

  59. Conceicao I, De Carvalho M. Clinical variability in type I familial amyloid polyneuropathy (Val30Met): comparison between late- and early-onset cases in Portugal. Muscle Nerve. 2007;35(1):116–8.

    CAS  PubMed  Google Scholar 

  60. Connors LH, Richardson AM, Theberge R, Costello CE. Tabulation of transthyretin (TTR) variants as of 1/1/2000. Amyloid. 2000;7(1):54–69.

    CAS  PubMed  Google Scholar 

  61. Suhr OB, Svendsen IH, Andersson R, Danielsson A, Holmgren G, Ranlov PJ. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Intern Med. 2003;254(3):225–35.

    CAS  PubMed  Google Scholar 

  62. Conceicao I, Damy T, Romero M, Galan L, Attarian S, Luigetti M, et al. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019;26(1):3–9.

    CAS  PubMed  Google Scholar 

  63. Obici L, Kuks JB, Buades J, Adams D, Suhr OB, Coelho T, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29(Suppl 1):S27–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Schmidt HH, Barroso F, Gonzalez-Duarte A, Conceicao I, Obici L, Keohane D, et al. Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2016;54(3):353–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gertz MA, Skinner M, Connors LH, Falk RH, Cohen AS, Kyle RA. Selective binding of nifedipine to amyloid fibrils. Am J Cardiol. 1985;55(13 Pt 1):1646.

    CAS  PubMed  Google Scholar 

  66. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J Cardiol. 1985;55(13 Pt 1):1645.

    CAS  PubMed  Google Scholar 

  67. Muchtar E, Gertz MA, Kumar SK, Lin G, Boilson B, Clavell A, et al. Digoxin use in systemic light-chain (AL) amyloidosis: contra-indicated or cautious use. Amyloid. 2018;25(2):86–92.

    CAS  PubMed  Google Scholar 

  68. Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet. 1991;40(3):242–6.

    CAS  PubMed  Google Scholar 

  69. Holmgren G, Ericzon BG, Groth CG, Steen L, Suhr O, Andersen O, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet. 1993;341(8853):1113–6.

    CAS  PubMed  Google Scholar 

  70. Wilczek HE, Larsson M, Ericzon BG. Long-term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). Amyloid. 2011;18(Suppl 1):193–5.

    PubMed  Google Scholar 

  71. Okamoto S, Zhao Y, Lindqvist P, Backman C, Ericzon BG, Wijayatunga P, et al. Development of cardiomyopathy after liver transplantation in Swedish hereditary transthyretin amyloidosis (ATTR) patients. Amyloid. 2011;18(4):200–5.

    CAS  PubMed  Google Scholar 

  72. Gustafsson S, Ihse E, Henein MY, Westermark P, Lindqvist P, Suhr OB. Amyloid fibril composition as a predictor of development of cardiomyopathy after liver transplantation for hereditary transthyretin amyloidosis. Transplantation. 2012;93(10):1017–23.

    CAS  PubMed  Google Scholar 

  73. Dubrey SW, Davidoff R, Skinner M, Bergethon P, Lewis D, Falk RH. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis. Transplantation. 1997;64(1):74–80.

    CAS  PubMed  Google Scholar 

  74. Garcia-Herola A, Prieto M, Pascual S, Berenguer M, Lopez-Viedma B, Mir J, et al. Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant. Liver Transpl Surg. 1999;5(3):246–8.

    CAS  PubMed  Google Scholar 

  75. Coelho T, Carvalho M, Saraiva MJ, Alves I, Almeida MR, Costa PP. A strikingly benign evolution of FAP in an individual compound heterozygote for two TTR mutations: TTR Met30 and TTR Met119. J Rheumatol. 1993;20:179.

  76. Hammarstrom P, Schneider F, Kelly JW. Trans-suppression of misfolding in an amyloid disease. Science. 2001;293(5539):2459–62.

    CAS  PubMed  Google Scholar 

  77. •• Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Plante-Bordeneuve V, Lozeron P, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–92 A randomized-controlled trial of 128 patients with ATTRv neuropathy randomized to tafamadis (TTR stabilizer) or placebo which did not meet primary end-point of trial but in secondary analyses showed significant delay in neurologic impairment.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Coelho T, Ines M, Conceicao I, Soares M, de Carvalho M, Costa J. Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy. Neurology. 2018;91(21):e1999–2009.

    CAS  PubMed  Google Scholar 

  79. •• Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. Jama. 2013;310(24):2658–67 The randomized-controlled trial of 130 patients with ATTRv polyneuropathy randomized to diflunisal or placebo showing efficacy of diflunisal in reducing neurologic progression and preserving quality of life at 2 years.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rosenblum H, Castano A, Alvarez J, Goldsmith J, Helmke S, Maurer MS. TTR (transthyretin) stabilizers are associated with improved survival in patients with TTR cardiac amyloidosis. Circ Heart Fail. 2018;11(4):e004769.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. •• 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 A recent randomized-controlled trial evaluating tafamadis vs. placebo in ATTR cardiac amyloidosis resulting in reduced all-cause mortality and cardiovascular-related hospitalizations in tafamadis treated patients, particularly in ATTRwt and NYHA I-II patients.

    CAS  PubMed  Google Scholar 

  82. •• 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 This phase 3 randomized-controlled trial evaluated intravenous patisiran vs. placebo in ATTR amyloidosis with polyneuropathy showed statistically significant improvements in multiple neurologic clinical metrics in patisiran-treated arm compared to placebo.

    CAS  PubMed  Google Scholar 

  83. Solomon SD, Adams D, Kristen A, Grogan M, Gonzalez-Duarte A, Maurer MS, et al. Effects of Patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation. 2019;139(4):431–43.

    CAS  PubMed  Google Scholar 

  84. •• Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotereson treatment for patients with hereditary transthyretic amyloidosis. N Engl J Med. 2018;379(11):22–31 This phase 3 randomized-controlled trial evaluated subcutaneous inotersen vs. placebo in ATTR amyloidosis with polyneuropathy showing improved course of neurologic disease in patients treated with inotersen compared to placebo controls.

    CAS  PubMed  Google Scholar 

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Funding

Dr. Gopal is supported by a career development grant from the American Heart Association (FTF 17FTF33670369). Dr. Ruberg is supported by the National Institutes of Health (R01 HL139671).

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Authors and Affiliations

  1. Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, 72 E. Concord Street, K-503, Boston, MA, 02118, USA

    Deepa M. Gopal, Frederick L. Ruberg & Omar K. Siddiqi

  2. Section of Cardiovascular Medicine, Boston University School of Medicine, Boston Medical Center, 72 E. Concord Street - Collamore, Boston, MA, 02118, USA

    Deepa M. Gopal, Frederick L. Ruberg & Omar K. Siddiqi

  3. Department of Radiology, Boston University School of Medicine, Boston Medical Center, 72 E. Concord Street, Boston, MA, 02118, USA

    Frederick L. Ruberg

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  1. Deepa M. Gopal
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Correspondence to Deepa M. Gopal.

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Dr. Ruberg and Dr. Gopal receive research funding from Eidos Therapeutics. Dr. Ruberg receives research and consulting income from Pfizer. Dr. Siddiqi has no conflicts to disclose.

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Gopal, D.M., Ruberg, F.L. & Siddiqi, O.K. Impact of Genetic Testing in Transthyretin (ATTR) Cardiac Amyloidosis. Curr Heart Fail Rep 16, 180–188 (2019). https://doi.org/10.1007/s11897-019-00436-z

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