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  • Review Article
  • Published:

Pathophysiology and treatment of cardiac amyloidosis

Nature Reviews Cardiology volume 12, pages 91–102 (2015)Cite this article

Subjects

Key Points

  • Cardiac amyloidosis should be suspected in any patient with heart failure and preserved ejection fraction or infiltrative cardiomyopathy

  • Histological diagnosis of amyloid requires further investigation to determine the protein subunit type, because the therapies vary widely

  • Preferred therapies for immunoglobulin light-chain amyloidosis involve standard-dose or high-dose chemotherapy with stem-cell rescue

  • Investigational therapies for transthyretin-related cardiomyopathy are diflunisal or tafamidis, and multiple new therapies for transthyretin-related amyloidosis and antibody therapy for immunoglobulin light-chain amyloidosis are being developed

Abstract

Amyloid cardiomyopathy should be suspected in any patient who presents with heart failure and preserved ejection fraction. In patients with echocardiographic evidence of ventricular thickening and without a clear history of hypertension, infiltrative cardiomyopathy should be considered. If imaging suggests the presence of amyloid deposits, confirmation by biopsy is required, although endomyocardial biopsy is generally not necessary. Assessment of aspirated subcutaneous fat and bone-marrow biopsy samples verifies the diagnosis in 40–80% of patients, dependent on the type of amyloidosis. Mass spectroscopy can be used to determine the protein subunit and classify the disease as immunoglobulin light-chain amyloidosis or transthyretin-related amyloidosis associated with mutant or wild-type TTR (formerly known as familial amyloid cardiomyopathy and senile cardiac amyloidosis, respectively). In this Review, we discuss the characteristics of cardiac amyloidosis, and present a structured approach to both the assessment of patients and treatment with emerging therapies and organ transplantation.

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Figure 1: Endomyocardial biopsy specimen.
Figure 2: Algorithm for diagnosis in patients with suspected amyloidosis.
Figure 3: Algorithm for diagnosis in patients with amyloidosis established by biopsy.

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References

  1. Gertz, M. A. 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. 79, 319–328 (2005).

    Article  PubMed  Google Scholar 

  2. Monge, M. et al. Localized amyloidosis of the genitourinary tract: report of 5 new cases and review of the literature. Medicine (Baltimore) 90, 212–222 (2011).

    Article  Google Scholar 

  3. Sommer, P., Kumar, G., Lipchik, R. J. & Patel, J. J. Tracheobronchial amyloidosis managed with multimodality therapies. Ther. Adv. Respir. Dis. 8, 48–52 (2014).

    Article  PubMed  Google Scholar 

  4. Gertz, M. A. Immunoglobulin light chain amyloidosis: update on diagnosis, prognosis, and treatment. Am. J. Hematol. 88, 416–425 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Sikkink, L. A. & Ramirez-Alvarado, M. Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture. Cell Death Dis. 1, e98 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Levinson, R. T. et al. Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes. Sci. Rep. 3, 1278 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ramirez-Alvarado, M. Amyloid formation in light chain amyloidosis. Curr. Top. Med. Chem. 12, 2523–2533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pinney, J. H. et al. Systemic amyloidosis in England: an epidemiological study. Br. J. Haematol. 161, 525–532 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bhole, M. V., Sadler, R. & Ramasamy, K. Serum-free light-chain assay: clinical utility and limitations. Ann. Clin. Biochem. 51, 528–542 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Kourelis, T. V. et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J. Clin. Oncol. 31, 4319–4324 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kyle, R. A. & Gertz, M. A. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin. Hematol. 32, 45–59 (1995).

    CAS  PubMed  Google Scholar 

  12. Anrade, C. A peculiar form of peripheral neuropathy: familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408–427 (1952).

    Article  Google Scholar 

  13. Azevedo, E. M., Scaff, M., Canelas, H. M. & Spina-Franca, A. Type I primary neuropathic amyloidosis [Portuguese]. Arq. Neuropsiquiatr. 33, 105–118 (1975).

    Article  CAS  PubMed  Google Scholar 

  14. Rowczenio, D. & Wechalekar, A. Mutations in hereditary amyloidosis [online], (2010).

    Google Scholar 

  15. Saraiva, M. J. Transthyretin mutations in health and disease. Hum. Mutat. 5, 191–196 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Rapezzi, C. et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 15, 40–48 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Zeldenrust, S. R. Genotype–phenotype correlation in FAP. Amyloid 19 (Suppl. 1), 22–24 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Sattianayagam, P. T. et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur. Heart J. 33, 1120–1127 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Arruda-Olson, A. M. et al. Genotype, echocardiography, and survival in familial transthyretin amyloidosis. Amyloid 20, 263–268 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Ruberg, F. L. 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. 164, 222–228.e1 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Reddi, H. V. et al. Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life. J. Mol. Diagn. 16, 68–74 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Pukitis, A. et al. Effect of infliximab induction therapy on secondary systemic amyloidosis associated with Crohn's disease: case report and review of the literature. J. Gastrointestin. Liver Dis. 22, 333–336 (2013).

    PubMed  Google Scholar 

  23. Kristen, A. V. et al. Transthyretin valine-94-alanine, a novel variant associated with late-onset systemic amyloidosis with cardiac involvement. Amyloid 14, 283–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Pinney, J. H. et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J. Am. Heart Assoc. 2, e000098 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Swiecicki, P. L. et al. Hereditary amyloidosis: a single-institution experience with 284 patients [abstract OP-53]. Presented at the XIVth International Symposium on Amyloidosis.

  26. Ng, B., Connors, L. H., Davidoff, R., Skinner, M. & Falk, R. H. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch. Intern. Med. 165, 1425–1429 (2005).

    Article  PubMed  Google Scholar 

  27. Takeda, M. et al. MRI differentiation of cardiomyopathy showing left ventricular hypertrophy and heart failure: differentiation between cardiac amyloidosis, hypertrophic cardiomyopathy, and hypertensive heart disease. Jpn. J. Radiol. 31, 693–700 (2013).

    Article  PubMed  Google Scholar 

  28. Mookadam, F., Haley, J. H., Olson, L. J., Cikes, M. & Mookadam, M. Dynamic left ventricular outflow tract obstruction in senile cardiac amyloidosis. Eur. J. Echocardiogr. 7, 465–468 (2006).

    Article  PubMed  Google Scholar 

  29. Potysova, Z. et al. Renal AA amyloidosis: survey of epidemiologic and laboratory data from one nephrology centre. Int. Urol. Nephrol. 41, 941–945 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Girnius, S., Dember, L., Doros, G. & Skinner, M. The changing face of AA amyloidosis: a single center experience. Amyloid 18 (Suppl. 1), 226–228 (2011).

    Article  PubMed  Google Scholar 

  31. Browning, M. J. et al. Ten years' experience of an amyloid clinic: a clinicopathological survey. Q. J. Med. 54, 213–227 (1985).

    CAS  PubMed  Google Scholar 

  32. Louros, N. N. et al. An N-terminal pro-atrial natriuretic peptide (NT-proANP) 'aggregation-prone' segment involved in isolated atrial amyloidosis. FEBS Lett. 588, 52–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Podduturi, V., Armstrong, D. R., Hitchcock, M. A., Roberts, W. C. & Guileyardo, J. M. Isolated atrial amyloidosis and the importance of molecular classification. Proc. (Bayl. Univ. Med. Cent.) 26, 387–389 (2013).

    Article  Google Scholar 

  34. Millucci, L. et al. Prevalence of isolated atrial amyloidosis in young patients affected by congestive heart failure. ScientificWorldJournal 2012, 293863 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ariyarajah, V. et al. The association of atrial tachyarrhythmias with isolated atrial amyloid disease: preliminary observations in autopsied heart specimens. Cardiology 113, 132–137 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Steensma, D. P. “Congo” red: out of Africa? Arch. Pathol. Lab. Med. 125, 250–252 (2001).

    CAS  PubMed  Google Scholar 

  37. Benson, M. D., Breall, J., Cummings, O. W. & Liepnieks, J. J. Biochemical characterisation of amyloid by endomyocardial biopsy. Amyloid 16, 9–14 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Arbustini, E. et al. Cardiac immunocyte-derived (AL) amyloidosis: an endomyocardial biopsy study in 11 patients. Am. Heart J. 130, 528–536 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Sloan, K. P., Bruce, C. J., Oh, J. K. & Rihal, C. S. Complications of echocardiography-guided endomyocardial biopsy. J. Am. Soc. Echocardiogr. 22, 324.e1–324.e4 (2009).

    Article  Google Scholar 

  40. Gertz, M. A. Immunoglobulin light chain amyloidosis: update on diagnosis, risk-stratification, and management. Am. J. Hematol. 86, 180–186 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Fine, N. M. et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis. Am. J. Cardiol. 113, 1723–1727 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Brambilla, F., Lavatelli, F., Merlini, G. & Mauri, P. Clinical proteomics for diagnosis and typing of systemic amyloidoses. Proteomics Clin. Appl. 7, 136–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Chee, C. E., Lacy, M. Q., Dogan, A., Zeldenrust, S. R. & Gertz, M. A. Pitfalls in the diagnosis of primary amyloidosis. Clin. Lymphoma Myeloma Leuk. 10, 177–180 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Maleszewski, J. J. et al. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc. Pathol. 22, 189–194 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Paueksakon, P., Fogo, A. B. & Sethi, S. Leukocyte chemotactic factor 2 amyloidosis cannot be reliably diagnosed by immunohistochemical staining. Hum. Pathol. 45, 1445–1450 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Mollee, P., Renaut, P., Gottlieb, D. & Goodman, H. How to diagnose amyloidosis. Intern. Med. J. 44, 7–17 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Hoshii, Y., Nanbara, H., Cui, D., Takahashi, M. & Ikeda, E. Immunohistochemical examination of Aκ amyloidosis with antibody against adjacent portion of the carboxy terminus of immunoglobulin kappa light chain. Med. Mol. Morphol. 45, 124–128 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Satoskar, A. A. et al. Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing. Am. J. Surg. Pathol. 35, 1685–1690 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Vrana, J. A. et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 114, 4957–4959 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Nasr, S. H. et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int. 83, 463–470 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Laffer, U. Intra-portal chemoprevention and therapy of liver metastases [German]. Z. Gastroenterol. Verh. 24, 189–191 (1989).

    CAS  PubMed  Google Scholar 

  52. Theis, J. D. et al. Proteome of amyloidosis: Mayo Clinic experience in 4139 cases [abstract OP-19] [online], (2014).

  53. Guan, J. et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res. Cardiol. 108, 378 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shi, J. et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway. Proc. Natl Acad. Sci. USA 107, 4188–4193 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Mohammed, S. F. et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2, 113–122 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Murtagh, B. et al. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am. J. Cardiol. 95, 535–537 (2005).

    Article  PubMed  Google Scholar 

  57. Mohty, D. et al. Cardiac amyloidosis: updates in diagnosis and management. Arch. Cardiovasc. Dis. 106, 528–540 (2013).

    Article  PubMed  Google Scholar 

  58. Russo, C., Green, P. & Maurer, M. The prognostic significance of central hemodynamics in patients with cardiac amyloidosis. Amyloid 20, 199–203 (2013).

    Article  PubMed  Google Scholar 

  59. Wittich, C. M., Neben-Wittich, M. A., Mueller, P. S., Gertz, M. A. & Edwards, W. D. Deposition of amyloid proteins in the epicardial coronary arteries of 58 patients with primary systemic amyloidosis. Cardiovasc. Pathol. 16, 75–78 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Seward, J. B. & Casaclang-Verzosa, G. Infiltrative cardiovascular diseases: cardiomyopathies that look alike. J. Am. Coll. Cardiol. 55, 1769–1779 (2010).

    Article  PubMed  Google Scholar 

  61. Bellavia, D. et al. Detection of left ventricular systolic dysfunction in cardiac amyloidosis with strain rate echocardiography. J. Am. Soc. Echocardiogr. 20, 1194–1202 (2007).

    Article  PubMed  Google Scholar 

  62. Buss, S. J. et al. Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers. J. Am. Coll. Cardiol. 60, 1067–1076 (2012).

    Article  PubMed  Google Scholar 

  63. Bellavia, D. et al. Evidence of impaired left ventricular systolic function by Doppler myocardial imaging in patients with systemic amyloidosis and no evidence of cardiac involvement by standard two-dimensional and Doppler echocardiography. Am. J. Cardiol. 101, 1039–1045 (2008).

    Article  PubMed  Google Scholar 

  64. Al-Zahrani, G. B. et al. Doppler myocardial imaging compared to standard two-dimensional and Doppler echocardiography for assessment of diastolic function in patients with systemic amyloidosis. J. Am. Soc. Echocardiogr. 22, 290–298 (2009).

    Article  PubMed  Google Scholar 

  65. Nesbitt, G. C. & Mankad, S. Strain and strain rate imaging in cardiomyopathy. Echocardiography 26, 337–344 (2009).

    Article  PubMed  Google Scholar 

  66. Bellavia, D. et al. Independent predictors of survival in primary systemic (AL) amyloidosis, including cardiac biomarkers and left ventricular strain imaging: an observational cohort study. J. Am. Soc. Echocardiogr. 23, 643–652 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bellavia, D. et al. Comparison of right ventricular longitudinal strain imaging, tricuspid annular plane systolic excursion, and cardiac biomarkers for early diagnosis of cardiac involvement and risk stratification in primary systematic (AL) amyloidosis: a 5-year cohort study. Eur. Heart J. Cardiovasc. Imaging 13, 680–689 (2012).

    Article  PubMed  Google Scholar 

  68. Lee, G. Y. et al. Cardiac amyloidosis without increased left ventricular wall thickness. Mayo Clin. Proc. 89, 781–789 (2014).

    Article  PubMed  Google Scholar 

  69. Suresh, R. et al. Advanced cardiac amyloidosis associated with normal interventricular spetal thickness: an uncommon presentation of infiltrative cardiomyopathy. J. Am. Soc. Echocardiogr. 27, 440–447 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Hazenberg, B. P. et al. Diagnostic performance and prognostic value of extravascular retention of 123I-labeled serum amyloid P component in systemic amyloidosis. J. Nucl. Med. 48, 865–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Hawkins, P. N. et al. Scintigraphic imaging and turnover studies with iodine-131 labelled serum amyloid P component in systemic amyloidosis. Eur. J. Nucl. Med. 25, 701–708 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Sachchithanantham, S. & Wechalekar, A. D. Imaging in systemic amyloidosis. Br. Med. Bull. 107, 41–56 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Bokhari, S. et al. 99mTc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ. Cardiovasc. Imaging 6, 195–201 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Gertz, M. A., Brown, M. L., Hauser, M. F. & Kyle, R. A. Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis. Arch. Intern. Med. 147, 1039–1044 (1987).

    Article  CAS  PubMed  Google Scholar 

  75. Aljaroudi, W. A. et al. Role of imaging in the diagnosis and management of patients with cardiac amyloidosis: state of the art review and focus on emerging nuclear techniques. J. Nucl. Cardiol. 21, 271–283 (2014).

    Article  PubMed  Google Scholar 

  76. Storandt, M., Mintun, M. A., Head, D. & Morris, J. C. Cognitive decline and brain volume loss as signatures of cerebral amyloid-β peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. Arch. Neurol. 66, 1476–1481 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Antoni, G. et al. In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET. J. Nucl. Med. 54, 213–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, J. et al. Noninvasive diagnosis of cardiac amyloidosis by MRI and echochardiography. J. Huazhong Univ. Sci. Technolog. Med. Sci. 30, 536–540 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Cheng, A. S., Banning, A. P., Mitchell, A. R., Neubauer, S. & Selvanayagam, J. B. Cardiac changes in systemic amyloidosis: visualisation by magnetic resonance imaging. Int. J. Cardiol. 113, E21–E23 (2006).

    Article  PubMed  Google Scholar 

  80. Aquaro, G. D. et al. Myocardial signal intensity decay after gadolinium injection: a fast and effective method for the diagnosis of cardiac amyloidosis. Int. J. Cardiovasc. Imaging 30, 1105–1115 (2014).

    Article  PubMed  Google Scholar 

  81. Pouchot, J. & Arlet, J. B. Biological treatment in adult-onset Still's disease. Best Pract. Res. Clin. Rheumatol. 26, 477–487 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Rubinshtein, R. et al. Comparison of magnetic resonance imaging versus Doppler echocardiography for the evaluation of left ventricular diastolic function in patients with cardiac amyloidosis. Am. J. Cardiol. 103, 718–723 (2009).

    Article  PubMed  Google Scholar 

  83. Syed, I. S. et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc. Imaging 3, 155–164 (2010).

    Article  PubMed  Google Scholar 

  84. Giesbrandt, K. J., Bolan, C. W., Shapiro, B. P., Edwards, W. D. & Mergo, P. J. Diffuse diseases of the myocardium: MRI-pathologic review of cardiomyopathies with dilatation. Am. J. Roentgenol. 200, W274–W282 (2013).

    Article  Google Scholar 

  85. Harvey-Taylor, J., Zhang, Y., Kuderer, V. & Cooke, D. T. Diagnosis of systemic amyloidosis and amyloidosis mediated cardiomyopathy by VATS pleural biopsy for chronic pleural effusion. J. Thorac. Dis. 5, E112–E114 (2013).

    PubMed  PubMed Central  Google Scholar 

  86. Finocchiaro, G. et al. Long term survival in patients with cardiac amyloidosis: prevalence and characterisation during follow-up. Heart Lung Circ. 22, 647–654 (2013).

    Article  PubMed  Google Scholar 

  87. Chaulagain, C. P. & Comenzo, R. L. New insights and modern treatment of AL amyloidosis. Curr. Hematol. Malig. Rep. 8, 291–298 (2013).

    Article  PubMed  Google Scholar 

  88. Dispenzieri, A. et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 104, 1881–1887 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Gertz, M. A. et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol. Dial. Transplant. 24, 3132–3137 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Park, M. A. et al. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore) 82, 291–298 (2003).

    Article  Google Scholar 

  91. Rajkumar, S. V., Gertz, M. A. & Kyle, R. A. Prognosis of patients with primary systemic amyloidosis who present with dominant neuropathy. Am. J. Med. 104, 232–237 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Dispenzieri, A. et al. High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis. Heart 100, 383–388 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Kumar, S. et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J. Clin. Oncol. 30, 989–995 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Halwani, O. & Delgado, D. H. Cardiac amyloidosis: an approach to diagnosis and management. Expert Rev. Cardiovasc. Ther. 8, 1007–1013 (2010).

    Article  PubMed  Google Scholar 

  95. Nash, K. L., Brij, S. O. & Clesham, G. J. Cardiac amyloidosis and the use of diuretic and ACE inhibitor therapy in severe heart failure. Int. J. Clin. Pract. 51, 384–385 (1997).

    CAS  PubMed  Google Scholar 

  96. Bouhour, J. B., Haddak, M. & Lefevre, M. Risks of beta-blockers and calcium inhibitors in amyloid cardiopathy [French]. Presse Med. 15, 981 (1986).

    CAS  PubMed  Google Scholar 

  97. Desport, E. et al. AL amyloidosis. Orphanet J. Rare Dis. 7, 54 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Lin, G., Dispenzieri, A., Kyle, R., Grogan, M. & Brady, P. A. Implantable cardioverter defibrillators in patients with cardiac amyloidosis. J. Cardiovasc. Electrophysiol. 24, 793–798 (2013).

    Article  PubMed  Google Scholar 

  99. Hess, E. P. & White, R. D. Out-of-hospital cardiac arrest in patients with cardiac amyloidosis: presenting rhythms, management and outcomes in four patients. Resuscitation 60, 105–111 (2004).

    Article  PubMed  Google Scholar 

  100. Swiecicki, P. L. et al. Left ventricular device implantation for advanced cardiac amyloidosis. J. Heart Lung Transplant. 32, 563–568 (2013).

    Article  PubMed  Google Scholar 

  101. Feng, D. et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation 116, 2420–2426 (2007).

    Article  PubMed  Google Scholar 

  102. Zubkov, A. Y., Rabinstein, A. A., Dispenzieri, A. & Wijdicks, E. F. Primary systemic amyloidosis with ischemic stroke as a presenting complication. Neurology 69, 1136–1141 (2007).

    Article  PubMed  Google Scholar 

  103. Feng, D. et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation 119, 2490–2497 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Kumar, S. K. et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin. Proc. 86, 12–18 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Gertz, M. A. How to manage primary amyloidosis. Leukemia 26, 191–198 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Nelson, M. R. et al. Histologic remission of cardiac amyloidosis: a case report. Amyloid 19, 106–109 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Palladini, G. et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J. Clin. Oncol. 30, 4541–4549 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Merlini, G., Seldin, D. C. & Gertz, M. A. Amyloidosis: pathogenesis and new therapeutic options. J. Clin. Oncol. 29, 1924–1933 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kumar, S. K. et al. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood 119, 4860–4867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tapan, U. et al. Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis. Blood 116, 5071–5072 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Mikhael, J. R. et al. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood 119, 4391–4394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Landau, H. et al. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia 27, 823–828 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Gertz, M. et al. Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis. Leuk. Lymphoma 49, 36–41 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Gertz, M. A. et al. Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis: outcomes before and after 2006. Bone Marrow Transplant. 46, 970–975 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Gertz, M. A. et al. Trend toward improved day 100 and two-year survival following stem cell transplantation for AL: a comparison before and after 2006. Amyloid 18 (Suppl. 1), 137–138 (2011).

    Article  PubMed  Google Scholar 

  116. Bellavia, D. et al. Utility of Doppler myocardial imaging, cardiac biomarkers, and clonal immunoglobulin genes to assess left ventricular performance and stratify risk following peripheral blood stem cell transplantation in patients with systemic light chain amyloidosis (AL). J. Am. Soc. Echocardiogr. 24, 444–454 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Singla, A. et al. Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation. Biol. Blood Marrow Transplant. 19, 1233–1237 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bleeker, J. S. et al. Evaluation of pretransplant factors predicting cardiac dysfunction following high-dose melphalan conditioning and autologous peripheral blood stem cell transplantation. Eur. J. Haematol. 89, 228–235 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Madan, S. et al. High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood 119, 1117–1122 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gertz, M. A. et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 48, 557–561 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Jimenez-Zepeda, V. H. et al. Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution. Br. J. Haematol. 164, 722–728 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Dispenzieri, A. et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 109, 465–470 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Dispenzieri, A. et al. Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs. Am. J. Hematol. 85, 757–759 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Dispenzieri, A. et al. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood 119, 5397–5404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Liedtke, M. et al. Preliminary cardiac biomarker responses demonstrated in an ongoing phase I study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction [abstract PB-48] [online], (2014).

  126. Gertz, M. A. & Dispenzieri, A. Immunoglobulin light-chain amyloidosis: growing recognition, new approaches to therapy, active clinical trials. Oncology (Williston Park) 26, 152–161 (2012).

    Google Scholar 

  127. Lacy, M. Q. et al. Autologous stem cell transplant after heart transplant for light chain (AL) amyloid cardiomyopathy. J. Heart Lung Transplant. 27, 823–829 (2008).

    Article  PubMed  Google Scholar 

  128. Gray Gilstrap, L. et al. Predictors of survival to orthotopic heart transplant in patients with light chain amyloidosis. J. Heart Lung Transplant. 33, 149–156 (2014).

    Article  PubMed  Google Scholar 

  129. Varr, B. C. et al. Heart transplantation and cardiac amyloidosis: approach to screening and novel management strategies. J. Heart Lung Transplant. 31, 325–331 (2012).

    Article  PubMed  Google Scholar 

  130. Raichlin, E. et al. Combined heart and liver transplantation: a single-center experience. Transplantation 88, 219–225 (2009).

    Article  PubMed  Google Scholar 

  131. Merlini, G. et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J. Cardiovasc. Transl. Res. 6, 1011–1020 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Coelho, T. et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J. Neurol. 260, 2802–2814 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Merlini, G. et al. Survival in patients with transthyretin familial amyloid polyneuropathy receiving tafamidis treatment [abstract OP-65]. Presented at the XIVth International Symposium on Amyloidosis.

  134. Maurer, M. S., Judge, D. P., Rosas, G. R., Mandel, F. S. & Aarts, J. Interim analysis of long-term, open-label tafamidis treatment in transthyretin amyloid cardiomyopathy after up to 5 years of treatment [abstract OP-66]. Presented at the XIVth International Symposium on Amyloidosis.

  135. Coelho, T. et al. Familial amyloid polyneuropathy treatment with tafamidis: evaluation of one year treatment at Porto, Portugal [abstract OP-67]. Presented at the XIVth International Symposium on Amyloidosis.

  136. Obici, L. et al. A phase II study of doxycycline plus tauroursodeoxycholic acid in transthyretin amyloidosis [abstract OP-68]. Presented at the XIVth International Symposium on Amyloidosis.

  137. Quarta, C. C. et al. The prevalence of cardiac amyloidosis in familial amyloidotic polyneuropathy with predominant neuropathy: the Diflunisal Trial [abstract OP-69]. Presented at the XIVth International Symposium on Amyloidosis.

  138. Berk, J. L. et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310, 2658–2667 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ackermann, E. J., Hughes, S., Yamashita, M. & Monia, B. P. Clinical development of ISIS-TTRRx: a second generation antisense therapy for the treatment of transthyretin-associated diseases [abstract OP-71]. Presented at the XIVth International Symposium on Amyloidosis.

  140. Suhr, O. et al. Further analysis of phase II trial of patisiran, a novel RNAi therapeutic for the treatment of familial amyloidotic polyneuropathy [abstract OP-72]. Presented at the XIVth International Symposium on Amyloidosis.

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Morie A. Gertz

  2. Division of Clinical Biochemistry and Immunology, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Angela Dispenzieri

  3. Division of Hematology/Oncology, Cancer Center, and Breast Clinic, Mayo Clinic, 4500 San Pablo Road, Jacksonville, 32224, FL, USA

    Taimur Sher

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  1. Morie A. Gertz
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  2. Angela Dispenzieri
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  3. Taimur Sher
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Contributions

M.A.G. researched data for the article, discussed its content, and wrote, reviewed, and edited the manuscript before submission. A.D. and T.S. also wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Morie A. Gertz.

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Competing interests

M.A.G. declares that he has received honoraria from Celgene, ISIS, Millennium, Neotope, Novartis, and Onyx. A.D. declares that she has received research funding from Celgene, Janssen, Millennium, and Pfizer. T.S. declares no competing interests.

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Gertz, M., Dispenzieri, A. & Sher, T. Pathophysiology and treatment of cardiac amyloidosis. Nat Rev Cardiol 12, 91–102 (2015). https://doi.org/10.1038/nrcardio.2014.165

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