Amyloidosis is a systemic disorder produced by the deposition of insoluble protein fibrils that fold and deposit in the myocardium. Patients with amyloidosis and cardiac involvement have higher mortality than patients without cardiac involvement. The two most prevalent forms of amyloidosis associated with cardiac involvement are AL amyloidosis, due to the deposition of immunoglobulin light chains, and ATTR amyloidosis, due to the deposition of the transthyretin (TTR) protein in mutated or senile form. This article aims to review the different cardiac imaging modalities (echocardiography, cardiac magnetic resonance imaging, nuclear medicine and tomography) that allow to determine the severity of cardiac involvement in patients with amyloidosis, the type of amyloidosis and its prognosis. Finally, we suggest a diagnostic algorithm to determine cardiac involvement in amyloidosis adapted to locally available diagnostic tools, with a practical and clinical approach.

1. Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: Evolving diagnosis and management: A scientific statement from the American Heart Association. Circulation 2020; 142: e7–e22. doi: 10.1161/CIR.0000000000000792.

2. Palladini G, Barassi A, Klersy C, et al. The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood 2010; 116(18): 3426–3430. doi: 10.1182/ blood-2010-05-286567.

3. Maurer M, Elliott P, Comenzo R, et al. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation 2017; 135(14): 1357–1377. doi: 10.1161/CIRCULATIONAHA.116.024438.

4. Jurcut R, Onciul S, Adam R, et al. Multimodality imaging in cardiac amyloidosis: a primer for cardiologists. European Heart Journal: Cardiovascular Imaging 2020; 21(8): 833–844. doi: 10.1093/ehjci/jeaa063.

5. García-Pavía P, Tomé-Esteban MT, Rapezzi C. Amyloidosis. Also a heart disease. Revista Española de Cardiología 2011; 64(9): 797–808. doi: 10.1016/j.recesp.2011.05.003.

6. Dorbala S, Cuddy S, Falk RH. How to image cardiac amyloidosis: A practical approach. JACC: Cardiovascular Imaging 2020; 13(6): 1368–1383. doi:10.1016/j.jcmg.2019.07.015.

7. González-López E, López-Sáinz Á, García-Pavia P. Diagnosis and treatment of transthyretin cardiac amyloidosis. Progress and hope. Revista Española de Cardiología 2017; 70(11): 991–1004. doi: 10.1016/j.recesp.2017.05.018.

8. Carroll J, Gaasch W, McAdam K. Amyloid cardiomyopathy: Characterization by a distinctive voltage/mass relation. American Journal of Cardiology 1982; 49(1): 9–13. doi: 10.1016/0002-9149(82)90270-3.

9. González-López E, Gagliardi C, Domínguez F, et al. Clinical characteristics of wild-type transthyretin cardiac amyloidosis: Disproving myths. European Heart Journal 2017; 38(24): 1895–1904.

10. doi: 10.1093/eurheartj/ehx043.

11. Phelan D, Thavendiranathan P, Popovic Z, et al. Application of a parametric display of two-dimen- sional speckle-tracking longitudinal strain to improve the etiologic diagnosis of mild to moderate left ventricular hypertrophy. Journal of the American Society of Echocardiography 2014; 27(8): 888–895. doi: 10.1016/j.echo.2014.04.015.

12. González-López E, Gagliardi C, Domínguez F, et al. Clinical characteristics of wild-type trans-thyretin cardiac amyloidosis: Disproving myths. European Heart Journal 2017; 38(24): 1895–1904.

13. doi: 10.1093/eurheartj/ehx043.

14. Helder MR, Schaff HV, Nishimura RA, et al. Impact of incidental amyloidosis on the prognosis of patients with hypertrophic cardiomyopathy undergoing septal myectomy for left ventricular outflow tract obstruction. American Journal of Cardiology 2014; 114(9): 1396–1399. doi: 10.1016/j.amjcard.2014.07.058.

15. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. JACC: Journal of the American College of Cardiology 2016; 68(10): 1014–1020. doi: 10.1016/j.jacc.2016.06.033.

16. Dubrey SW, Cha K, Skinner M, et al. Familial and primary (AL) cardiac amyloidosis: Echocardio- graphically similar diseases with distinctly different clinical outcomes. Heart 1997; 78(1): 74–82. doi: 10.1136/hrt.78.1.74.

17. Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC State-of-the-Art Review. Journal of the American College of Cardiology 2019; 73(22): 2872–2891. doi: 10.1016/j.jacc.2019.04.00.

18. Cueto-Garcia L, Reeder GS, Kyle RA, et al. Echocardiographic findings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. Journal of the American College of Cardiology 1985; 6(4): 1737–1743. doi: 10.1016/S0735-1097(85)80475-7.

19. Habib G, Bucciarelli-Ducci C, Caforio ALP, et al. EACVI Scientific Documents Committee. Multimodality imaging in restrictive cardiomyopathies: An EACVI expert consensus document in collaboration with the “Working Group on myocardial and pericardial diseases” of the European Society of Cardiology Endorsed by The Indian Academy of Echocardiography. European Heart Journal: Cardiovascular Imaging 2017; 18(10): 1090–1121. doi: 10.1093/ehjci/jex034.

20. Koyama J, Ray-Sequin PA, Davidoff R, et al. Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. American Journal of Cardiology 2002; 89(9): 1067–1071. doi: 10.1016/S0002-9149(02)02277-4.

21. Quarta CC, Solomon SD, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 2014; 129(18): 1840–1849. doi: 10.1161/CIRCULATIONAHA.113.006242.

22. Liu D, Hu K, Nordbeck P, et al. Longitudinal strain bull’s eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy. European Journal of Medical Research 2016; 21: 21. doi: 10.1186/s40001-016-0216-y.

23. Koyam J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain amyloidosis. Journal of the American College of Cardiology Imaging 2010; 3(4): 333–342. doi: 10.1016/j.jcmg.2009.11.013.

24. 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. Circulation: Cardiovascular Imaging 2013; 6(6): 1066–1072. doi: 10.1161/CIRCIMAGING.113.000683.

25. Pagourelias ED, Mirea O, Duchenne J, et al. Echo parameters for differential diagnosis in cardiac amyloidosis: A head-to-head comparison of deformation and non-deformation parameters. Circulation: Cardiovascular Imaging 2017; 10(3): e005588. doi: 10.1161/CIRCIMAGING.116.005588.

26. Bodez DT, Guellich A, Galat A, et al. Prognostic value of right ventricular systolic function in cardiac amyloidosis. Amyloidosis 2016; 23(3): 158–167. doi: 10.1 080/13506129.2016.1194264.

27. Bellavia D, Pellikka PA, Dispenzieri A, 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. European Heart Journal: Cardiovascular Imaging 2012; 13(8): 680–669. doi: 10.1093/ehjci/jes009.

28. Fikrle M, Paleček T, Kuchynka P, et al. Cardiac amyloidosis: A comprehensive review. Cor et Vasa 2013; 55(1): e60-e75. doi: 10.1016/j.crvasa.2012.11.018.

29. Mohty D, Pradel S, Magne J, et al. Prevalence and prognostic impact of left-sided valve thickening in systemic light-chain amyloidosis. Clinical Research in Cardiology 2017; 106(5): 331–340.

30. doi: 10.1007/s00392-016-1058-x.

31. González-López E, López-Sáinz Á, García-Pavia P. Diagnosis and treatment of transthyretin cardiac amyloidosis. Progress and hope. Revista Española de Cardiología 2017; 70(11): 991–1004. doi: 10.1016/j.recesp.2017.05.018.

32. Castaño A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. European Heart Journal 2017; 38(38): 2879–2887. doi: 10.1093/eurheartj/ehx350.

33. Falk RH, Alexander KM, Liao R, et al. AL (light-chain) cardiac amyloidosis: A review of diagnosis and therapy. Journal of the American College of Cardiology 2016; 68(12): 1323–1341. doi: 10.1016/j.jacc.2016.06.053.

34. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography 2016; 29(4): 1321–1360. doi: 10.1093/ehjci/jew082.

35. Klein AL, Hatle LK, Taliercio CP, et al. Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echo-cardiography study. Circulation 1991; 83(3): 808–816. doi: 10.1161/01.CIR.83.3.808.

36. Schiano-Lomoriello V, Galderisi M, Mele D, et al. Longitudinal strain of left ventricular basal segments and E/e0 ratio differentiate primary cardiac amyloidosis at presentation from hypertensive hypertrophy: An automated function imaging study. Echocardiography 2016; 33(9): 1335–1343. doi: 10.1111/echo.13278.

37. 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. Circulation: Cardiovascular Imaging 2013; 6(6): 1066–1072. doi: 10.1161/CIRCIMAGING.113.000683.

38. Zhao L, Tian Z, Fang Q. Risk factors and prognostic role of left atrial enlargement in patients with cardiac light-chain amyloidosis. American Journal of the Medical Sciences 2016; 351(3): 271–278. doi: 10.1016/j.amjms.2015.12.015.

39. Mohty D, Pibarot P, Dumesnil JG, et al. Left atrial size is an independent predictor of overall survival in patients with primary systemic amyloidosis. Archives of Cardiovascular Diseases 2011; 104(12): 611–618. doi: 10.1016/j.acvd.2011.10.004.

40. Falk RH, Plehn JF, Deering T, et al. Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. American Journal of Cardiology 1987; 59(5): 418–422. doi: 10.1016/0002-9149(87)90948-9.

41. Santarone M, Corrado G, Tagliagambe LM, et al. Atrial thrombosis in cardiac amyloidosis: Diagnostic contribution of transesophageal echocardiography. Journal of the American Society of Echocardiography 1999; 12(6): 533–536. doi: 10.1016/S0894-7317(99)70091-X.

42. Feng D, Edwards WD, Oh JK, et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation 2007; 116(21): 2420–2426. doi: 10.1161/CIRCULATIONAHA.107.697763.

43. Baccouche H, Maunz M, Beck T, et al. Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three-dimensional speckle tracking echocardiography. Echocardiography 2012; 29(6): 668–677. doi: 10.1111/j.1540-8175.2012.01680.x.

44. Mohty D, Petitalot V, Magne J, et al. Left atrial function in patients with light chain amyloidosis: A transthoracic 3D speckle tracking imaging study. Journal of Cardiology 2018; 71(4): 419–427. doi: 10.1016/j.jjcc.2017.10.007.

45. Fine NM, Davis MK, Anderson K, et al. Canadian Cardiovascular Society. Canadian heart failure society joint position statement on the evaluation and management of patients with cardiac amyloidosis. Canadian Journal of Cardiology 2020; 36(3): 322–334. doi: 10.1016/j.cjca.2019.12.034.

46. Zhao L, Tian Z, Fang Q. Diagnostic accuracy of cardiovascular magnetic resonance imaging for patients with suspected cardiac amyloidosis: A systematic review and meta-analysis. BMC Cardiovascular Disorders 2016; 16: 129. doi: 10.1186/s12872-016-0311-6.

47. Baroni M, Nava S, Quattrocchi G, et al. Role of cardiovascular magnetic resonance in suspected cardiac amyloidosis: Late gadolinium enhancement pattern as mortality predictor. Netherlands Heart Journal 2018; 26(1): 34–40. doi: 10.1007/s12471-017-1046-4.

48. Dungu JN, Valencia O, Pinney JH, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC: Cardiovascular Imaging 2014; 7(2): 132–142. doi: 10.1016/j.jcmg.2013.08.015.

49. White J, Kim H, Shah D, et al. CMR imaging with rapid visual T1 assessment predicts mortality in patients suspected of cardiac amyloidosis. JACC Cardiovasc Imaging 2014; 7(2): 143–56. doi: 10.1016/j.jcmg.2013.09.019.

50. Fontana M, Banypersad SM, Treibel TA, et al. Native T1 mapping in transthyretin amyloidosis. JACC: Cardiovascular Imaging 2014; 7(2): 157–165. doi: 10.1016/j.jcmg.2013.10.008.

51. Messroghli DR, Moon JC, Ferreira VM, et al. Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI). Journal of Cardiovascular Magnetic Resonance 2017; 19: 75. doi: 10.1186/s12968-017-0389-8.

52. Fontana M, Banypersad SM, Treibel TA, et al. Differential myocyte responses in patients with cardic transthyretin amyloidosis and light-chain amyloidosis: A cardiac MR imaging study. Radiology 2015; 277(2): 388–397. doi: 10.1148/radiol.2015141744.

53. Martinez-Naharro A, Abdel-Gadir A, Treibel TA, et al. CMR-verified regression of cardiac AL amyloid after chemotherapy. JACC: Cardiovascular Imaging 2018; 11(1): 152–154. doi: 10.1016/j.jcmg.2017.02.012.

54. Ridouani F, Damy T, Tacher V, et al. Myocardial native T2 measurement to differentiate light chain and transthyretin cardiac amyloidosis and assess prognosis. Journal of Cardiovascular Magnetic Resonance 2018; 20: 58. doi: 10.1186/s12968-018-0478-3.

55. Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance imaging: a report of the American college of cardiology foundation task force on expert consensus documents. Circulation 2010; 121(22): 2462–2508. doi: 10.1161/CIR.0b013e3181d44a8f.

56. Baggiano A, Boldrini M, Martinez-Naharro A, et al. Noncontrast magnetic resonance for the diagnosis of cardiac amyloidosis. JACC: Cardiovascular Imaging 2020; 13(1): 69–80. doi: 10.1016/j.jcmg.2019.03.026.

57. Singh V FR, Di Carli MF, Kijewski M, et al. State-of-the-art radionuclide imaging in cardiac transthyretin amyloidosis. Journal of Nuclear Cardiology 2019; 26(1): 158–173. doi: 10.1007/s12350-018-01552-4.

58. Masri A, Bukhari S, Eisele Y, et al. Molecular imaging of cardiac amyloidosis. Journal of Nuclear Medicine 2020; 61(7): 965–970.

59. doi: 10.2967/jnumed.120.245381.

60. Siddiqi O, Ruberg F. Cardiac amyloidosis: An update on pathophysiology, diagnosis and treatment. Trends in Cardiovascular Medicine 2018; 28: 10–21. doi: 10.1016/j.tcm.2017.07.004.

61. Guillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016; 133(24): 2404–2412. doi: 10.1161/CIRCULATIONAHA.116.021612.

62. Treglia G, Glaudemans A, Bertagna F, et al. Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: A bivariate meta-analysis. European Journal of Nuclear Medicine and Molecular Imaging 2018; 45(11): 1945–1955. doi: 10.1007/s00259-018-4013-4.

63. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 1 of 2-Diagnostic criteria and appropriate utilization. Journal of Nuclear Cardiology 2019; 26(6): 2065–2123. doi: 10.1007/s12350-019-01760-6.

64. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 2 of 2-Diagnostic criteria and appropriate utilization. Journal of Nuclear Cardiology 2020; 27(2): 659–673. doi: 10.1007/s12350-019-01761-5.

65. Daquarti GJ, Meretta A, Corneli M, et al. Bone seeking tracers’ scintigraphy for the diagnosis of transthyretin cardiac amyloidosis. Medicine 2018; 78(6): 395–398.

66. Falk RH, Quarta CC, Dorbala S. How to image cardiac amyloidosis: A practicle approach. Circulation: Cardiovascular Imaging 2014; 7(3): 553–562. doi: 10.1161/CIRCIMAGING.113.001396.

67. Stats MA, Stone JR. Varying levels of small microcalcifications and macrophages in ATTR and AL cardiac amyloidosis: Implications for utilizing nuclear medicine studies to subtype amyloidosis. Cardiovascular Pathology 2016; 25(5): 413–417. doi: 10.1016/j.carpath.2016.07.001.

68. Dorbala S, Bokhari S, Miller E, et al. American Society of Nuclear Cardiology (ASNC) practice points on technetium-99m pyrophosphate imaging for transthyretin cardiac amyloidosis. 1st ed. Fairfax: American Society of Nuclear Cardiology; 2019.

69. Dorbala S, Bokhari S, Glaudemans AW, et al. American Society of Nuclear Cardiology (ASNC) and European Association of Nuclear Medicine practice points on 99mTechnetium-3,3-diphos-pho- no-1,2-propanodicarboxylic acid (DPD) and 99mTechnetium-hydroxymethylene diphosphonate (HMDP) imaging for transthyretin cardiac amyloidosis. 1st ed. Fairfax: American Society of Nuclear Cardiology; 2019.

70. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scinitigraphy. Journal of the American College of Cardiology 2005; 46(6): 1076–1084. doi: 10.1016/j. jacc.2005.05.073.

71. Bokhari S, Castaño A, Pozniakoff T, et al. 99mTc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circulation: Cardiovascular Imaging 2013; 6(2): 195–201. doi: 10.1161/CIRCIMAGING.112.000132.

72. Campisi R, Traverso SS. Diagnosis of transthyretin cardiac amyloidosis with cadium zinc telluride cameras: Is it feasible? Journal of Nuclear Cardiology 2020; 27: 381–385. doi: 10.1007/s12350-020-02071-x.

73. De Graaf FR, Schuijf JD, Delgado V, et al. Clinical application of CT coronary angiography: State of the art. Heart, Lung and Circulation 2010; 19(3): 107–116. doi: 10.1016/j.hlc.2009.11.004.

74. Lin FY, Devereux RB, Roman MJ, et al. Cardiac chamber volumes, function, and mass as determined by 64-multidetector row computed tomography: Mean values among healthy adults free of hypertension and obesity. JACC: Cardiovascular Imaging 2008; 1(6): 782–786. doi: 10.1016/j.jcmg.2008.04.015.

75. Henneman MM, Bax JJ, Schuijf JD, et al. Global and regional left ventricular function: A comparison between gated SPECT, 2D echocardiography and multi-slice computed tomography. European Journal of Nuclear Medicine and Molecular Imaging 2006; 33(12): 1452–1460. doi: 10.1007/s00259-006-0158-7.

76. Treibel TA, Fontana M, Gilbertson JA, et al. Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: Prevalence and prognosis in patients undergoing surgical aortic valve replacement. Circulation: Cardiovascular Imaging 2016; 9(8): e005066. doi: 10.1161/CIRCIMAGING.116.005066.

77. Scully PR, Treibel TA, Fontana M, et al. Prevalence of cardiac amyloidosis in patients referred for transcatheter aortic valve replacement. Journal of the American College of Cardiology 2018; 71(4): 463–464. doi: 10.1016/j.jacc.2017.11.037.

78. Castaño A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. European Heart Journal 2017; 38(38): 2879–2887. doi: 10.1093/eurheartj/ehx350.

79. Scully PR, Bastarrika G, Moon JC, et al. Myocardial extra-cellular volume quantification by cardiovascu- lar magnetic resonance and computed tomography. Current Cardiology Reports 2018; 20(3): 15.

80. doi: 10.1007/s11886-018-0961-3.

81. Sado DM, Flett AS, Banypersad SM, et al. Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart 2012; 98(19): 1436–1441. doi: 10.1136/heartjnl-2012-302346.

82. Treibel TA, Fontana M, Steeden JA, et al. Automatic quantification of the myocardial extracellular volume by cardiac computed tomography: Synthetic ECV by CCT. Journal of Cardiovascular Computed Tomography 2017; 11(3): 221–226. doi: 10.1016/j.jcct.2017.02.006.

83. Bandula S, White SK, Flett AS, et al. Measurement of myocardial extracellular volume fraction by using equilibrium contrast-enhanced CT: Validation against histologic findings. Radiology 2013; 269(2): 396–403. doi: 10.1148/radiol.13130130.

84. Rosmini S, Treibel TA, Bandula S, et al. Cardiac computed tomography for the detection of cardiac amyloidosis. Journal of Cardiovascular Computed Tomography 2017; 11(2): 155–156. doi: 10.1016/j.jcct.2016.09.001.