Advances in Treatment of Cardiac Amyloid

  • Cherie N. Dahm
  • R. Frank Cornell
  • Daniel J. Lenihan
Cardio-oncology (M Fradley, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cardio-oncology


Systemic amyloidosis represents a complex group of diseases with a common feature characterized by misfolded autologous proteins depositing into tissues or organs throughout the body. Light chain amyloidosis (AL) and transthyretin (TTR) amyloid are the two most prevalent forms of this disease that commonly results in cardiac amyloidosis. In both of these conditions, the myocardium is a frequent site of infiltration and end-organ involvement often with devastating consequences. With cardiac amyloidosis becoming an increasingly identified disease that has previously been under-recognized, the purpose of this comprehensive review is to focus on the diagnosis and treatment of these two types of cardiac amyloidosis including a contemporary update on currently available therapies being investigated in clinical trials. Subsequently, we will detail potential therapeutic efficacy and limitations of these regimens, and then complete the review by highlighting newer treatment modalities. A high-level overview of modern therapeutic approaches for AL amyloid includes targeted therapies directed at reducing the production of precursor proteins and inhibitors intended to limit the deposition of fibrils in tissues. In the case of TTR amyloid, current therapy is focused on stabilization of TTR proteins, suppression of protein formation, and blocking the deposition of amyloid fibrils in tissue. Novel therapies are focused on removing amyloid fibril deposition from affected tissues. In summary, cardiac amyloidosis is a progressively devastating disease requiring swift recognition and treatment now with groundbreaking therapies on the horizon.


Systemic amyloidosis Cardio-oncology Light chain amyloidosis Transthyretin 


Compliance with Ethical Standards

Conflict of Interest

Cherie N. Dahm and R. Frank Cornell each declare no potential conflicts of interest.

Daniel J. Lenihan reports research support from Takeda and is a consultant for Roche, BMS, Prothera, Amgen, Takeda, and Janssen.

Human and Animal Rights and Informed Consent

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

References and Recommended Reading

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

  1. 1.
    Sipe JD, Cohen AS. Review: history of the amyloid fibril. J Struct Biol. 2000;130(2–3):88–98.CrossRefPubMedGoogle Scholar
  2. 2.
    Freudenthaler S, Hegenbart U, Schönland S, Behrens HM, Krüger S, Röcken C. Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients. Virchows Arch. 2016;468(5):569–77.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Maleszewski JJ. Cardiac amyloidosis: pathology, nomenclature, and typing. Cardiovasc Pathol. 2015;24(6):343–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Yusuf SW, Solhpour A, Banchs J, et al. Cardiac amyloidosis. Expert Rev Cardiovasc Ther. 2014;12(2):265–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989–95.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Grogan M, Dispenzieri A, Gertz MA. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 2017;103(14):1065–72.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Merlini G, Planté-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res. 2013;6(6):1011–20.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–67.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Falk RH, Alexander KM, Liao R, Dorbala S. AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol. 2016;68(12):1323–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Gertz MA, Comenzo R, Falk RH, et al. 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, Tours, France, 18–22 April 2004. Am J Hematol. 2005;79(4):319–28.CrossRefPubMedGoogle Scholar
  11. 11.
    Bhogal S, Ladia V, Sitwala P, et al. Cardiac amyloidosis: an updated review with emphasis on diagnosis and future directions. Curr Probl Cardiol. 2018;43(1):10–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Mohty D, Damy T, Cosnay P, et al. Cardiac amyloidosis: updates in diagnosis and management. Arch Cardiovasc Dis. 2013;106(10):528–40.CrossRefPubMedGoogle Scholar
  13. 13.
    Piper C, Butz T, Farr M, Faber L, Oldenburg O, Horstkotte D. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Liu D, Hu K, Niemann M, et al. Effect of combined systolic and diastolic functional parameter assessment for differentiation of cardiac amyloidosis from other causes of concentric left ventricular hypertrophy. Circ Cardiovasc Imaging. 2013;6(6):1066–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Senapati A, Sperry BW, Grodin JL, et al. Prognostic implication of relative regional strain ratio in cardiac amyloidosis. Heart. 2016;102(10):748–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Pagourelias ED, Duchenne J, Mirea O, et al. The relation of ejection fraction and global longitudinal strain in amyloidosis: implications for differential diagnosis. JACC Cardiovasc Imaging. 2016;9(11):1358–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Boynton SJ, Geske JB, Dispenzieri A, et al. LGE provides incremental prognostic information over serum biomarkers in AL cardiac amyloidosis. JACC Cardiovasc Imaging. 2016;9(6):680–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404–12.CrossRefPubMedGoogle Scholar
  20. 20.
    Castano A, Haq M, Narotsky DL, 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
  21. 21.
    Dorbala S, Vangala D, Semer J, et al. Imaging cardiac amyloidosis: a pilot study using 18F-florbetapir positron emission tomography. Eur J Nucl Med Mol Imaging. 2014;41(9):1652–62.CrossRefPubMedGoogle Scholar
  22. 22.
    Siddiqi OK, Ruberg FL. Challenging the myths of cardiac amyloidosis. Eur Heart J. 2017;38(24):1909–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Gertz MA, Li CY, Shirahama T, Kyle RA. Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Arch Intern Med. 1988;148(4):929–33.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Pollak A, Falk RH. Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest. 1993;104(2):618–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Geller HI, Singh A, Mirto TM, et al. Prevalence of monoclonal gammopathy in wild-type transthyretin amyloidosis. Mayo Clin Proc. 2017;92(12):1800–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346(23):1786–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Meier-Ewert HK, Sanchorawala V, Berk JL, Ruberg FL. Cardiac amyloidosis: evolving approach to diagnosis and management. Curr Treat Options Cardiovasc Med. 2011;13(6):528–42.CrossRefPubMedGoogle Scholar
  29. 29.
    Tan NY, Mohsin Y, Hodge DO, et al. Catheter ablation for atrial arrhythmias in patients with cardiac amyloidosis. J Cardiovasc Electrophysiol. 2016;27(10):1167–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Maurer MS, Elliott P, Merlini G, et al. Design and rationale of the phase 3 ATTR-ACT clinical trial (tafamidis in transthyretin cardiomyopathy clinical trial). Circ Heart Fail. 2017;10(6)Google Scholar
  31. 31.
    Suhr OB, Coelho T, Buades 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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016;44(14):6549–63.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wechalekar AD, Whelan C. Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. Blood Cancer J. 2017;7(3):e546.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012;19(Suppl 1):34–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Higaki JN, Chakrabartty A, Galant NJ, et al. Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. J Protein Fold Disord. 2016;23(2):86–97.CrossRefGoogle Scholar
  36. 36.
    Madan S, Kumar SK, Dispenzieri A, et al. High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood. 2012;119(5):1117–22.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317–25.CrossRefPubMedGoogle Scholar
  38. 38.
    Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012;119(19):4391–4.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jaccard A, Comenzo RL, Hari P, et al. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014;99(9):1479–85.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jaccard A. POEMS syndrome: therapeutic options. Hematol Oncol Clin N Am. 2018;32(1):141–51.CrossRefGoogle Scholar
  41. 41.
    Nozza A, Terenghi F, Gallia F, et al. Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective, open-label trial. Br J Haematol. 2017;179(5):748–55.CrossRefPubMedGoogle Scholar
  42. 42.
    Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012;119(23):5397–404.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cohen AD, Scott EC, Liedtke M, et al. A phase I dose-escalation study of carfilzomib in patients with previously-treated systemic light-chain (AL) amyloidosis. Blood. 2014;124:4741.Google Scholar
  44. 44.
    Merlini G, Sanchorawala V, Jeffrey ZA, et al. Long-term outcome of a phase 1 study of the investigational oral proteasome inhibitor (PI) ixazomib at the recommended phase 3 dose (RP3D) in patients (Pts) with relapsed or refractory systemic light-chain (AL) amyloidosis (RRAL). Blood. 2014;124:3450.CrossRefGoogle Scholar
  45. 45.
    Langer AL, Miao S, Mapara M, et al. Results of a phase 1 study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis. Blood. 2015;126:188.Google Scholar
  46. 46.
    Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase I/II study of NEOD001 in Patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097–103.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Edwards CV, Gould J, Langer AL, et al. Final analysis of the phase 1a/b study of chimeric fibril-reactive monoclonaL ANTIBODY 11-1F4 in patients with relapsed or refractory AL amyloidosis. Am Soc Hematol. 2017;1(30):509.Google Scholar
  48. 48.
    Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086–97.CrossRefPubMedGoogle Scholar
  49. 49.
    Bulawa CE, Connelly S, Devit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012;109(24):9629–34.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Castaño A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail. 2012;18(6):315–9.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Penchala SC, Connelly S, Wang Y, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U SA. 2013;110(24):9992–7.CrossRefGoogle Scholar
  52. 52.
    • Adams D, Gonzalez-Duarte A, O’Riordan W, et al. Patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR amyloidosis with polyneuropathy: results from the phase 3 APOLLO study. EU ATTR Meeting- Paris. 2017. Includes the most up to date findings on treatment of TTR amyloidosis with both showing an improvement in quality of life. Both drugs showed significant stabilization/improvement in cardiac structure/function.Google Scholar
  53. 53.
    Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625–38.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    •• slideshow. Includes the most up to date findings on treatment of TTR amyloidosis with both showing an improvement in quality of life. Both drugs showed significant stabilization/improvement in cardiac structure/function.
  55. 55.
    Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of familial amyloidotic polyneuropathy. Biochim Biophys Acta. 2008;1782(9):517–22.CrossRefPubMedGoogle Scholar
  56. 56.
    Oluchi U, Tarsheen S, Goodman S, et al. Autologous hematopoietic cell transplant (AHCT) offers prolonged progression free and overall survival in patients with light chain amyloidosis (AL) compared with chemotherapy alone. Biol Blood Marrow Transplant. 2016;22(3):233–4.CrossRefGoogle Scholar
  57. 57.
    Cornell RF, Zhong X, Arce-Lara C, et al. Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation. Bone Marrow Transplant. 2015;50(7):914–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. 2015;33(12):1371–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Muchtar E, Dispenzieri A, Kumar SK, et al. Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category. Leukemia. 2017;31(7):1562–9.CrossRefPubMedGoogle Scholar
  60. 60.
    D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417–21.CrossRefPubMedGoogle Scholar
  61. 61.
    Kaufmann G, Witteles R, Wheeler M, et al. Hematologic responses and cardiac organ improvement in patients with heavily pretreated cardiac immunoglobulin light chain (AL) amyloidosis receiving daratumumab. Blood. 2016;128:abstr 4525.Google Scholar
  62. 62.
    Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? Blood. 2016;128(2):159–68.CrossRefPubMedGoogle Scholar
  63. 63.
    Pepys MB, Dash AC. Isolation of amyloid P component (protein AP) from normal serum as a calcium-dependent binding protein. Lancet. 1977;1(8020):1029–31.CrossRefPubMedGoogle Scholar
  64. 64.
    Hamon D, Algalarrondo V, Gandjbakhch E, et al. Outcome and incidence of appropriate implantable cardioverter-defibrillator therapy in patients with cardiac amyloidosis. Int J Cardiol. 2016;222:562–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Lin G, Dispenzieri A, Kyle R, Grogan M, Brady PA. Implantable cardioverter defibrillators in patients with cardiac amyloidosis. J Cardiovasc Electrophysiol. 2013;24(7):793–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet. 1993;341(8853):1113–6.CrossRefPubMedGoogle Scholar
  67. 67.
    Dubrey SW, Burke MM, Khaghani A, Hawkins PN, Yacoub MH, Banner NR. Long term results of heart transplantation in patients with amyloid heart disease. Heart. 2001;85(2):202–7.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Dey BR, Chung SS, Spitzer TR, et al. Cardiac transplantation followed by dose-intensive melphalan and autologous stem-cell transplantation for light chain amyloidosis and heart failure. Transplantation. 2010;90(8):905–11.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gray Gilstrap L, Niehaus E, Malhotra R, et al. Predictors of survival to orthotopic heart transplant in patients with light chain amyloidosis. J Heart Lung Transplant. 2014;33(2):149–56.CrossRefPubMedGoogle Scholar
  70. 70.
    Mehra MR, Canter CE, Hannan MM, et al. Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant. 2016;35(1):1–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication April/2018

Authors and Affiliations

  • Cherie N. Dahm
    • 1
  • R. Frank Cornell
    • 2
  • Daniel J. Lenihan
    • 3
  1. 1.Department of Internal MedicineVanderbilt University Medical CenterNashvilleUSA
  2. 2.Division of Hematology and OncologyVanderbilt University Medical CenterNashvilleUSA
  3. 3.Cardiovascular Division, Cardio-Oncology Center of ExcellenceWashington University in St LouisSt LouisUSA

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