Cardiac Amyloidosis

  • Carmela D. TanEmail author
  • E. Rene Rodriguez
Part of the Current Clinical Pathology book series (CCPATH)


Involvement of the cardiovascular system by amyloid deposits can be a localized phenomenon or part of a systemic disease. Isolated atrial, valvular, and aortic amyloidoses are in most instances asymptomatic and incidental findings in surgical specimens. Symptomatic cardiac amyloidosis is due to deposition of immunoglobulin light chains or transthyretin in the majority of cases. Except for familial transthyretin-associated amyloidosis, the heart is rarely involved in other hereditary types of amyloidosis. Cardiac amyloidosis is an underdiagnosed cause of heart failure. While electrocardiographic, echocardiographic, and magnetic resonance imaging findings could be highly suspicious for amyloidosis, definitive diagnosis and amyloid typing require an endomyocardial biopsy. The typical gross and microscopic features of cardiac amyloidosis are presented, as well as potential pitfalls and caveats in amyloid typing. Identifying the correct amyloid protein type is important for therapeutic management and prognostication. Early diagnosis remains a challenging problem. The prognosis of patients with cardiac amyloidosis is still poor because of advanced stage at the time of diagnosis and limited effectiveness of current treatment modalities.


Light chain amyloidosis Transthyretin amyloidosis Atrial Valvular Aortic Senile systemic amyloidosis Light chain deposition disease Atrial natriuretic factor Apolipoprotein A1 Endomyocardial biopsy 


  1. 1.
    Steiner I. The prevalence of isolated atrial amyloid. J Pathol. 1987;153:395–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Cornwell 3rd GG, Murdoch WL, Kyle RA, et al. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med. 1983;75:618–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Steiner I, Hajkova P. Patterns of isolated atrial amyloid: a study of 100 hearts on autopsy. Cardiovasc Pathol. 2006;15:287–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Kawamura S, Takahashi M, Ishihara T, et al. Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts. Pathol Int. 1995;45:335–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Pucci A, Wharton J, Arbustini E, et al. Atrial amyloid deposits in the failing human heart display both atrial and brain natriuretic peptide-like immunoreactivity. J Pathol. 1991;165:235–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Rocken C, Peters B, Juenemann G, et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation. 2002;106:2091–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Leone O, Boriani G, Chiappini B, et al. Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation. Eur Heart J. 2004;25:1237–41.CrossRefPubMedGoogle Scholar
  8. 8.
    Mucchiano G, Cornwell 3rd GG, Westermark P. Senile aortic amyloid: evidence for two distinct forms of localized deposits. Am J Pathol. 1992;140:871–7.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Haggqvist B, Naslund J, Sletten K, et al. Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid. Proc Natl Acad Sci USA. 1999;96:8669–74.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Peng S, Glennert J, Westermark P. Medin-amyloid: a recently characterized age-associated arterial amyloid form affects mainly arteries in the upper part of the body. Amyloid. 2005;12:96–102.CrossRefPubMedGoogle Scholar
  11. 11.
    Peng S, Larsson A, Wassberg E, et al. Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection. Lab Invest. 2007;87:1195–205.CrossRefPubMedGoogle Scholar
  12. 12.
    Mucchiano GI, Haggqvist B, Sletten K, et al. Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta. J Pathol. 2001;193:270–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Goffin Y. Microscopic amyloid deposits in the heart valves: a common local complication of chronic damage and scarring. J Clin Pathol. 1980;33:262–8.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Cooper JH. Localized dystrophic amyloidosis of heart valves. Hum Pathol. 1983;14:649–53.CrossRefPubMedGoogle Scholar
  15. 15.
    Ladefoged C, Rohr N. Amyloid deposits in aortic and mitral valves. A clinicopathological investigation of material from 100 consecutive heart valve operations. Virchows Arch A Pathol Anat Histopathol. 1984;404:301–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Kristen AV, Schnabel PA, Winter B, et al. High prevalence of amyloid in 150 surgically removed heart valves—a comparison of histological and clinical data reveals a correlation to atheroinflammatory conditions. Cardiovasc Pathol. 2010;19:228–35.CrossRefPubMedGoogle Scholar
  17. 17.
    Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore). 2008;87:99–109.CrossRefGoogle Scholar
  18. 18.
    Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM. 1998;91:141–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005;165:1425–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120:1203–12.CrossRefPubMedGoogle Scholar
  21. 21.
    Guan J, Mishra S, Shi J, et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol. 2013;108:378.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Westermark P, Bergstrom J, Solomon A, et al. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003;10 Suppl 1:48–54.PubMedGoogle Scholar
  23. 23.
    Pitkanen P, Westermark P, Cornwell III GG. Senile systemic amyloidosis. Am J Pathol. 1984;117:391–9.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Olson LJ, Gertz MA, Edwards WD, et al. Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med. 1987;317:738–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Hattori T, Takei Y, Koyama J, et al. Clinical and pathological studies of cardiac amyloidosis in transthyretin type familial amyloid polyneuropathy. Amyloid. 2003;10:229–39.CrossRefPubMedGoogle Scholar
  26. 26.
    Ihse E, Ybo A, Suhr O, et al. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J Pathol. 2008;216:253–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Strege RJ, Saeger W, Linke RP. Diagnosis and immunohistochemical classification of systemic amyloidoses. Report of 43 cases in an unselected autopsy series. Virchows Arch. 1998;433:19–27.CrossRefPubMedGoogle Scholar
  28. 28.
    Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–71.CrossRefPubMedGoogle Scholar
  29. 29.
    Gal R, Korzets A, Schwartz A, et al. Systemic distribution of beta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysis. Report of seven cases and review of the literature. Arch Pathol Lab Med. 1994;118:718–21.PubMedGoogle Scholar
  30. 30.
    Ohashi K, Takagawa R, Hara M. Visceral organ involvement and extracellular matrix changes in beta 2-microglobulin amyloidosis—a comparative study with systemic AA and AL amyloidosis. Virchows Arch. 1997;430:479–87.CrossRefPubMedGoogle Scholar
  31. 31.
    Rowczenio D, Dogan A, Theis JD, et al. Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. Am J Pathol. 2011;179:1978–87.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation. Blood. 2010;115:2998–3007.CrossRefPubMedGoogle Scholar
  33. 33.
    Neben-Wittich MA, Wittich CM, Mueller PS, et al. Obstructive intramural coronary amyloidosis and myocardial ischemia are common in primary amyloidosis. Am J Med. 2005;118:1287.CrossRefPubMedGoogle Scholar
  34. 34.
    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;30:989–95.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Bokhari S, Castaño A, Pozniakoff T, et al. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidosis. Circ Cardiovasc Imaging. 2013;6:195–201.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Antoni G, Lubberink M, Estrada S, et al. In vivo visualization of amyloid deposits in the heart with 11CPIB and PET. J Nucl Med. 2013;54:213–20.CrossRefPubMedGoogle Scholar
  37. 37.
    Dorbala S, Vangala D, Semer J, et al. Imaging cardiac amyloidosis: a pilot study using (18)F-florbetapir positron emission tomography. Eur J Nucl Med Mol Imaging. 2014;41:1652–62.CrossRefPubMedGoogle Scholar
  38. 38.
    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;79:319–28.CrossRefPubMedGoogle Scholar
  39. 39.
    Yazaki M, Liepnieks JJ, Barats MS, et al. Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg. Kidney Int. 2003;64:11–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Maury CP. Gelsolin-related amyloidosis. Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin. J Clin Invest. 1991;87:1195–9.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac dysfunction: analysis of 54 necropsy patients. Am J Cardiol. 1983;52:137–46.CrossRefPubMedGoogle Scholar
  42. 42.
    Bergstrom J, Gustavsson A, Hellman U, et al. Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology. J Pathol. 2005;206:224–32.CrossRefPubMedGoogle Scholar
  43. 43.
    Westermark GT, Johnson KH, Westermark P. Staining methods for identification of amyloid in tissue. Methods Enzymol. 1999;309:3–25.CrossRefPubMedGoogle Scholar
  44. 44.
    Crotty TB, Li CY, Edwards WD, et al. Amyloidosis and endomyocardial biopsy: correlation of extent and pattern of deposition with amyloid immunophenotype in 100 cases. Cardiovasc Pathol. 1995;4:39–42.CrossRefPubMedGoogle Scholar
  45. 45.
    Kieninger B, Eriksson M, Kandolf R, et al. Amyloid in endomyocardial biopsies. Virchows Arch. 2010;456:523–32.CrossRefPubMedGoogle Scholar
  46. 46.
    Collins AB, Smith RN, Stone JR. Classification of amyloid deposits in diagnostic cardiac specimens by immunofluorescence. Cardiovasc Pathol. 2009;18:205–16.CrossRefPubMedGoogle Scholar
  47. 47.
    Kebbel A, Rocken C. Immunohistochemical classification of amyloid in surgical pathology revisited. Am J Surg Pathol. 2006;30:673–83.CrossRefPubMedGoogle Scholar
  48. 48.
    Palladini G, Obici L, Merlini G. Hereditary amyloidosis. N Engl J Med. 2002;347:1206–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Benson MD, Breall J, Cummings OW, et al. Biochemical characterization of amyloid by endomyocardial biopsy. Amyloid. 2009;16:9–14.CrossRefPubMedGoogle Scholar
  50. 50.
    Murphy CL, Eulitz M, Hrncic R, et al. Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens. Am J Clin Pathol. 2001;116:135–42.CrossRefPubMedGoogle Scholar
  51. 51.
    Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Picken MM. Modern approaches to the treatment of amyloidosis: the critical importance of early detection in surgical pathology. Adv Anat Pathol. 2013;20:424–39.CrossRefPubMedGoogle Scholar
  53. 53.
    Buxbaum JN, Genega EM, Lazowski P, et al. Infiltrative nonamyloidotic monoclonal immunoglobulin light chain cardiomyopathy: an underappreciated manifestation of plasma cell dyscrasias. Cardiology. 2000;93:220–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Toor AA, Ramdane BA, Joseph J, et al. Cardiac nonamyloidotic immunoglobulin deposition disease. Mod Pathol. 2006;19:233–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Maleszewski JJ, Murray DL, Dispenzieri A, Grogan M, Pereira NL, Jenkins SM, Judge DP, Caturegli P, Vrana JA, Theis JD, Dogan A, Halushka MK. Relationship between monoclonal gammopathy and cardiac amyloid type. Cardiovasc Pathol. 2013;22:189–94.CrossRefPubMedGoogle Scholar
  56. 56.
    Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346:1786–91.CrossRefPubMedGoogle Scholar
  57. 57.
    Comenzo RL, Zhou P, Fleisher M, et al. Seeking confidence in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. Blood. 2006;107:3489–91.CrossRefPubMedGoogle Scholar
  58. 58.
    de Sousa MM, Vital C, Ostler D, et al. Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis. Am J Pathol. 2000;156:1911–7.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Hanna M. Novel drugs targeting transthyretin amyloidosis. Curr Heart Fail Rep. 2014;11:50–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med. 1996;101:395–400.CrossRefPubMedGoogle Scholar
  61. 61.
    Ruberg FL, Maurer MS, JUdge DP, 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;164:222–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of PathologyCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA

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