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Advances in the diagnosis and treatment of transthyretin amyloidosis with cardiac involvement

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Abstract

Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils constituted by misfolded proteins, which can modify tissue anatomy and hinder the function of multiple organs including the heart. Amyloidosis that can affect the heart includes mostly systemic amyloidosis (amyloid light chain, AL) and transthyretin amyloidosis (ATTR). The latter can be acquired in elderly patients (ATTRwt), or be inherited in younger individuals (ATTRm). The diagnosis is demanding given the high phenotypic heterogeneity of the disease. Therefore, “red flags,” which are suggestive features giving support to diagnostic suspicion, are extremely valuable. However, the lack of broad awareness among clinicians represents a major obstacle for early diagnosis and treatment of ATTR. Furthermore, recent implementation of noninvasive diagnostic techniques has revisited the need for endomyocardial biopsy (EMB). In fact, unlike AL amyloidosis, which requires tissue confirmation and typing for diagnosis, ATTR can now be diagnosed noninvasively with the combination of bone scintigraphy and the absence of a monoclonal protein. Securing the correct diagnosis is pivotal for the newly available therapeutic options targeting both ATTRm and ATTRwt, and are directed to either stabilization of the abnormal protein or the reduction of the production of transthyretin. The purpose of this article is to review the contemporary aspects of diagnosis and management of transthyretin amyloidosis with cardiac involvement, summarizing also the recent therapeutic advances with tafamidis, patisiran, and inotersen.

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Abbreviations

[99mTc]-DPD:

Tc-99m-3,3-diphosphono-1,2-propanodicarboxylic acid

[99mTc]-HMDP:

Tc-99m-hydroxymethylene diphosphonate

[99mTc]-PYP:

Tc-99m-pyrophosphate

123I-MIBG:

123I-Metaiodobenzylguanidine

AL:

Light chain amyloidosis

ANP:

Atrial natriuretic peptide

AS:

Aortic stenosis

ATTR:

Transthyretin amyloidosis

ATTRm:

Mutant transthyretin amyloidosis

ATTRwt:

Wild-type transthyretin amyloidosis

BNP:

Brain natriuretic peptide

CA:

Cardiac amyloidosis

CMR:

Cardiac magnetic resonance

cTnT:

Cardiac troponin T

ECG:

Electrocardiography

EMB:

Endomyocardial biopsy

EF:

Ejection fraction

EFSR:

Ejection fraction strain ratio

GLS:

Global longitudinal strain

HCM:

Hypertrophic cardiomyopathy

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

KCCQ-OS:

Kansas City Cardiomyopathy Questionnaire-Overall Summary

LFLG:

Low-flow low-gradient

LGE:

Late gadolinium enhancement

LV:

Left ventricular

LVH:

Left ventricular hypertrophy

LVOT:

Left ventricular outflow tract

Norfolk QOL-DN:

Norfolk Quality of Life-Diabetic Neuropathy

NT-proBNP:

N-terminal pro-brain natriuretic peptide

PET:

Positron emission tomography

RBP4:

Retinol binding protein 4

RCM:

Restrictive cardiomyopathy

RV:

Right ventricular

SCD:

Sudden cardiac death

ST:

Speckle-tracking

TAVI:

Transcatheter aortic valve implantation

TDI:

Tissue Doppler imaging

TTR:

Transthyretin

References

  1. Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P (2016) Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid 23(4):209–213

    Article  CAS  PubMed  Google Scholar 

  2. Mankad AK, Shah KB (2017) Transthyretin cardiac amyloidosis. Curr Cardiol Rep 19(10):97

    Article  PubMed  Google Scholar 

  3. Sanders P, Morton JB, Davidson NC, Spence SJ, Vohra JK, Sparks PB, Kalman JM (2003) Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation 108(12):1461–1468

    Article  PubMed  Google Scholar 

  4. Leone O, Boriani G, Chiappini B, Pacini D, Cenacchi G, Martin Suarez S, Rapezzi C, Bacchi Reggiani ML, Marinelli G (2004) Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation. Eur Heart J 25(14):1237–1241

    Article  CAS  PubMed  Google Scholar 

  5. Dubrey SW, Cha K, Simms RW, Skinner M, Falk RH (1996) Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol 77(4):313–315

    Article  CAS  PubMed  Google Scholar 

  6. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM (2014) Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2(2):113–122

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L (2008) Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 40(3):232–239

    Article  CAS  PubMed  Google Scholar 

  8. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C (2017) Addressing common questions encountered in the diagnosis and Management of Cardiac Amyloidosis. Circulation 135(14):1357–1377

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cornwell GG III, Murdoch WL, Kyle RA, Westermark P, Pitkanen P (1983) Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 75(4):618–623

    Article  PubMed  Google Scholar 

  10. Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW (2002) Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 99(Suppl 4):16427–16432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Castano A, Drachman BM, Judge D, Maurer MS (2015) Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 20(2):163–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M, Berk JL, Plante-Bordeneuve V, Schmidt HHJ, Merlini G (2015) Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 66(21):2451–2466

    Article  CAS  PubMed  Google Scholar 

  13. Barbero U, Destefanis P (2015) An Indian-look right into restrictive cardiomyopathies. Indian Heart J 67(6):512–513

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rammos A, Meladinis V, Vovas G, Patsouras D (2017) Restrictive cardiomyopathies: the importance of noninvasive cardiac imaging modalities in diagnosis and treatment-a systematic review. Radiol Res Pract 2017:2874902

    PubMed  PubMed Central  Google Scholar 

  15. Westphal JG, Rigopoulos AG, Bakogiannis C, Ludwig SE, Mavrogeni S, Bigalke B, Doenst T, Pauschinger M, Tschope C, Schulze PC, Noutsias M (2017) The MOGE(S) classification for cardiomyopathies: current status and future outlook. Heart Fail Rev 22(6):743–752

    Article  PubMed  Google Scholar 

  16. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN (2016) Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 133(24):2404–2412

    Article  CAS  PubMed  Google Scholar 

  17. Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, Pozniakoff T, Ruberg FL, Miller EJ, Berk JL, Dispenzieri A, Grogan M, Johnson G, Bokhari S, Maurer MS (2016) Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis. JAMA Cardiol 1(8):880–889

    Article  PubMed  Google Scholar 

  18. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P (2015) Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 36(38):2585–2594

    Article  CAS  PubMed  Google Scholar 

  19. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C, Investigators A-AS (2018) Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 379(11):1007–1016

    Article  CAS  PubMed  Google Scholar 

  20. Castano A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, Rubin J, Chiuzan C, Nazif T, Vahl T, George I, Kodali S, Leon MB, Hahn R, Bokhari S, Maurer MS (2017) Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J 38(38):2879–2887

    Article  PubMed  PubMed Central  Google Scholar 

  21. Damy T, Costes B, Hagege AA, Donal E, Eicher JC, Slama M, Guellich A, Rappeneau S, Gueffet JP, Logeart D, Plante-Bordeneuve V, Bouvaist H, Huttin O, Mulak G, Dubois-Rande JL, Goossens M, Canoui-Poitrine F, Buxbaum JN (2016) Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J 37(23):1826–1834

    Article  PubMed  Google Scholar 

  22. Connors LH, Prokaeva T, Lim A, Theberge R, Falk RH, Doros G, Berg A, Costello CE, O’Hara C, Seldin DC, Skinner M (2009) Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 158(4):607–614

    Article  CAS  PubMed  Google Scholar 

  23. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A (2016) Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol 68(10):1014–1020

    Article  PubMed  Google Scholar 

  24. Rapezzi C, Lorenzini M, Longhi S, Milandri A, Gagliardi C, Bartolomei I, Salvi F, Maurer MS (2015) Cardiac amyloidosis: the great pretender. Heart Fail Rev 20(2):117–124

    Article  CAS  PubMed  Google Scholar 

  25. Nativi-Nicolau J, Maurer MS (2018) Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. Curr Opin Cardiol 33(5):571–579

    PubMed  Google Scholar 

  26. Gonzalez-Lopez E, Gagliardi C, Dominguez F, Quarta CC, de Haro-Del Moral FJ, Milandri A, Salas C, Cinelli M, Cobo-Marcos M, Lorenzini M, Lara-Pezzi E, Foffi S, Alonso-Pulpon L, Rapezzi C, Garcia-Pavia P (2017) Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths. Eur Heart J 38(24):1895–1904

    Article  CAS  PubMed  Google Scholar 

  27. Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, Biagini E, Lorenzini M, Grigioni F, Leone O, Cappelli F, Palladini G, Rimessi P, Ferlini A, Arpesella G, Pinna AD, Merlini G, Perlini S (2013) Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 34(7):520–528

    Article  CAS  PubMed  Google Scholar 

  28. Qian G, Wu C, Zhang Y, Chen YD, Dong W, Ren YH (2014) Prognostic value of high-sensitivity cardiac troponin T in patients with endomyocardial-biopsy proven cardiac amyloidosis. J Geriatr Cardiol 11(2):136–140

    PubMed  PubMed Central  Google Scholar 

  29. Lehrke S, Steen H, Kristen AV, Merten C, Lossnitzer D, Dengler TJ, Katus HA, Giannitsis E (2009) Serum levels of NT-proBNP as surrogate for cardiac amyloid burden: new evidence from gadolinium-enhanced cardiac magnetic resonance imaging in patients with amyloidosis. Amyloid 16(4):187–195

    Article  CAS  PubMed  Google Scholar 

  30. Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB, Damy T, investigators T (2017) Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One 12(4):e0173086

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, Lane T, Gilbertson JA, Rowczenio D, Petrie A, Hawkins PN (2018) A new staging system for cardiac transthyretin amyloidosis. Eur Heart J 39(30):2799–2806

    Article  CAS  PubMed  Google Scholar 

  32. Buxbaum J, Anan I, Suhr O (2010) Serum transthyretin levels in Swedish TTR V30M carriers. Amyloid 17(2):83–85

    Article  CAS  PubMed  Google Scholar 

  33. Arvanitis M, Simon S, Chan G, Fine D, Beardsley P, LaValley M, Jacobson D, Koch C, Berk JL, Connors LH, Ruberg FL (2017) Retinol binding protein 4 (RBP4) concentration identifies V122I transthyretin cardiac amyloidosis. Amyloid 24(sup1):120–121

    Article  PubMed  PubMed Central  Google Scholar 

  34. Arvanitis M, Koch CM, Chan GG, Torres-Arancivia C, LaValley MP, Jacobson DR, Berk JL, Connors LH, Ruberg FL (2017) Identification of transthyretin cardiac amyloidosis using serum retinol-binding protein 4 and a clinical prediction model. JAMA Cardiol 2(3):305–313

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mints YY, Doros G, Berk JL, Connors LH, Ruberg FL (2018) Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience. ESC Heart Fail 5(5):772–779

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cardim N, Galderisi M, Edvardsen T, Plein S, Popescu BA, D’Andrea A, Bruder O, Cosyns B, Davin L, Donal E, Freitas A, Habib G, Kitsiou A, Petersen SE, Schroeder S, Lancellotti P, Camici P, Dulgheru R, Hagendorff A, Lombardi M, Muraru D, Sicari R (2015) Role of multimodality cardiac imaging in the management of patients with hypertrophic cardiomyopathy: an expert consensus of the European Association of Cardiovascular Imaging Endorsed by the Saudi Heart Association. Eur Heart J Cardiovasc Imaging 16(3):280

    Article  PubMed  Google Scholar 

  37. Ha JW, Ommen SR, Tajik AJ, Barnes ME, Ammash NM, Gertz MA, Seward JB, Oh JK (2004) Differentiation of constrictive pericarditis from restrictive cardiomyopathy using mitral annular velocity by tissue Doppler echocardiography. Am J Cardiol 94(3):316–319

    Article  PubMed  Google Scholar 

  38. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN (2012) Cardiac transthyretin amyloidosis. Heart 98(21):1546–1554

    Article  PubMed  Google Scholar 

  39. Suresh R, Grogan M, Maleszewski JJ, Pellikka PA, Hanna M, Dispenzieri A, Pereira NL (2014) Advanced cardiac amyloidosis associated with normal interventricular septal thickness: an uncommon presentation of infiltrative cardiomyopathy. J Am Soc Echocardiogr 27(4):440–447

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pozo E, Kanwar A, Deochand R, Castellano JM, Naib T, Pazos-Lopez P, Osman K, Cham M, Narula J, Fuster V, Sanz J (2014) Cardiac magnetic resonance evaluation of left ventricular remodelling distribution in cardiac amyloidosis. Heart 100(21):1688–1695

    Article  PubMed  Google Scholar 

  41. Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD (2012) Updates in cardiac amyloidosis: a review. J Am Heart Assoc 1(2):e000364

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tei C, Dujardin KS, Hodge DO, Kyle RA, Tajik AJ, Seward JB (1996) Doppler index combining systolic and diastolic myocardial performance: clinical value in cardiac amyloidosis. J Am Coll Cardiol 28(3):658–664

    Article  CAS  PubMed  Google Scholar 

  43. Cacciapuoti F (2015) The role of echocardiography in the non-invasive diagnosis of cardiac amyloidosis. J Echocardiogr 13(3):84–89

    Article  PubMed  Google Scholar 

  44. Phelan D, Collier P, Thavendiranathan P, Popovic ZB, Hanna M, Plana JC, Marwick TH, Thomas JD (2012) Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 98(19):1442–1448

    Article  PubMed  Google Scholar 

  45. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, Gagliardi C, Milandri A, Rapezzi C, Falk RH (2014) Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation 129(18):1840–1849

    Article  PubMed  Google Scholar 

  46. Habib G, Bucciarelli-Ducci C, ALP C, Cardim N, Charron P, Cosyns B, Dehaene A, Derumeaux G, Donal E, Dweck MR, Edvardsen T, Erba PA, Ernande L, Gaemperli O, Galderisi M, Grapsa J, Jacquier A, Klingel K, Lancellotti P, Neglia D, Pepe A, Perrone-Filardi P, Petersen SE, Plein S, Popescu BA, Reant P, Sade LE, Salaun E, Slart R, Tribouilloy C, Zamorano J, Committee ESD, Indian Academy of E (2017) 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. Eur Heart J Cardiovasc Imaging 18(10):1090–1121

    Article  PubMed  Google Scholar 

  47. Arvidsson S, Henein MY, Wikstrom G, Suhr OB, Lindqvist P (2018) Right ventricular involvement in transthyretin amyloidosis. Amyloid 25:160–166

  48. Sun JP, Stewart WJ, Yang XS, Donnell RO, Leon AR, Felner JM, Thomas JD, Merlino JD (2009) Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography. Am J Cardiol 103(3):411–415

    Article  PubMed  Google Scholar 

  49. Pagourelias ED, Duchenne J, Mirea O, Vovas G, Van Cleemput J, Delforge M, Kuznetsova T, Bogaert J, Voigt JU (2016) The relation of ejection fraction and global longitudinal strain in amyloidosis: implications for differential diagnosis. JACC Cardiovasc Imaging 9(11):1358–1359

    Article  PubMed  Google Scholar 

  50. Baccouche H, Maunz M, Beck T, Gaa E, Banzhaf M, Knayer U, Fogarassy P, Beyer M (2012) Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three-dimensional speckle tracking echocardiography. Echocardiography 29(6):668–677

    Article  PubMed  Google Scholar 

  51. Henein MY, Suhr OB, Arvidsson S, Pilebro B, Westermark P, Hornsten R, Lindqvist P (2018) Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis. Amyloid 25(1):46–53

    Article  CAS  PubMed  Google Scholar 

  52. Haloui F, Salaun E, Maysou L, Dehaene A, Habib G (2016) Cardiac amyloidosis: an unusual cause of low flow-low gradient aortic stenosis with preserved ejection fraction. Eur Heart J Cardiovasc Imaging 17(4):383

    Article  PubMed  Google Scholar 

  53. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, Whelan CJ, Myerson SG, Robson MD, Hawkins PN, Neubauer S, Moon JC (2013) Noncontrast T1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 6(4):488–497

    Article  PubMed  Google Scholar 

  54. Di Bella G, Minutoli F, Mazzeo A, Vita G, Oreto G, Carerj S, Anfuso C, Russo M, Gaeta M (2010) MRI of cardiac involvement in transthyretin familial amyloid polyneuropathy. AJR Am J Roentgenol 195(6):W394–W399

    Article  PubMed  Google Scholar 

  55. Williams LK, Forero JF, Popovic ZB, Phelan D, Delgado D, Rakowski H, Wintersperger BJ, Thavendiranathan P (2017) Patterns of CMR measured longitudinal strain and its association with late gadolinium enhancement in patients with cardiac amyloidosis and its mimics. J Cardiovasc Magn Reson 19(1):61

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pozo E, Castellano JM, Kanwar A, Deochand R, Castillo-Martin M, Pazos-Lopez P, Gonzalez-Lengua C, Osman K, Cham M, Cordon-Cardo C, Narula J, Fuster V, Sanz J (2018) Myocardial amyloid quantification with look-locker magnetic resonance sequence in cardiac amyloidosis. Diagnostic accuracy in clinical practice and histological validation. J Card Fail 24(2):78–86

    Article  CAS  PubMed  Google Scholar 

  57. Fontana M, Banypersad SM, Treibel TA, Maestrini V, Sado DM, White SK, Pica S, Castelletti S, Piechnik SK, Robson MD, Gilbertson JA, Rowczenio D, Hutt DF, Lachmann HJ, Wechalekar AD, Whelan CJ, Gillmore JD, Hawkins PN, Moon JC (2014) Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imaging 7(2):157–165

    Article  PubMed  Google Scholar 

  58. Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, Ferlini A, Longhi S, Lorenzini M, Reggiani LB, Gagliardi C, Gallo P, Villani C, Salvi F (2011) Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging 4(6):659–670

    Article  PubMed  Google Scholar 

  59. Noordzij W, Glaudemans AW, Longhi S, Slart RH, Lorenzini M, Hazenberg BP, Rapezzi C (2015) Nuclear imaging for cardiac amyloidosis. Heart Fail Rev 20(2):145–154

    Article  CAS  PubMed  Google Scholar 

  60. Glaudemans AW, van Rheenen RW, van den Berg MP, Noordzij W, Koole M, Blokzijl H, Dierckx RA, Slart RH, Hazenberg BP (2014) Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid 21(1):35–44

    Article  CAS  PubMed  Google Scholar 

  61. Morgenstern R, Yeh R, Castano A, Maurer MS, Bokhari S (2018) (18)Fluorine sodium fluoride positron emission tomography, a potential biomarker of transthyretin cardiac amyloidosis. J Nucl Cardiol 25(5):1559–1567

    Article  PubMed  Google Scholar 

  62. Ezawa N, Katoh N, Oguchi K, Yoshinaga T, Yazaki M, Sekijima Y (2018) Visualization of multiple organ amyloid involvement in systemic amyloidosis using (11)C-PiB PET imaging. Eur J Nucl Med Mol Imaging 45(3):452–461

    Article  PubMed  Google Scholar 

  63. Hongo M, Urushibata K, Kai R, Takahashi W, Koizumi T, Uchikawa S, Imamura H, Kinoshita O, Owa M, Fujii T (2002) Iodine-123 metaiodobenzylguanidine scintigraphic analysis of myocardial sympathetic innervation in patients with AL (primary) amyloidosis. Am Heart J 144(1):122–129

    Article  CAS  PubMed  Google Scholar 

  64. Noordzij W, Glaudemans AW, van Rheenen RW, Hazenberg BP, Tio RA, Dierckx RA, Slart RH (2012) (123)I-Labelled metaiodobenzylguanidine for the evaluation of cardiac sympathetic denervation in early stage amyloidosis. Eur J Nucl Med Mol Imaging 39(10):1609–1617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Misumi Y, Ueda M, Yamashita T, Masuda T, Kinoshita Y, Tasaki M, Nagase T, Ando Y (2017) Novel screening for transthyretin amyloidosis by using fat ultrasonography. Ann Neurol 81(4):604–608

    Article  CAS  PubMed  Google Scholar 

  66. Dahlem K, Michels G, Kobe C, Bunck AC, Ten Freyhaus H, Pfister R (2017) Diagnosis of cardiac transthyretin amyloidosis based on multimodality imaging. Clin Res Cardiol 106(6):471–473

    Article  PubMed  Google Scholar 

  67. Fine NM, Arruda-Olson AM, Dispenzieri A, Zeldenrust SR, Gertz MA, Kyle RA, Swiecicki PL, Scott CG, Grogan M (2014) Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis. Am J Cardiol 113(10):1723–1727

    Article  CAS  PubMed  Google Scholar 

  68. Ruberg FL, Berk JL (2012) Transthyretin (TTR) cardiac amyloidosis. Circulation 126(10):1286–1300

    Article  PubMed  PubMed Central  Google Scholar 

  69. Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ, Gottlieb SS, Shah SJ, Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, Hummel SL, Kristen AV, Damy T, Plante-Bordeneuve V, Coelho T, Mundayat R, Suhr OB, Waddington Cruz M, Rapezzi C, Investigators T (2016) Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol 68(2):161–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Damy T, Maurer MS, Rapezzi C, Plante-Bordeneuve V, Karayal ON, Mundayat R, Suhr OB, Kristen AV (2016) Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy. Open Heart 3(1):e000289

    Article  PubMed  PubMed Central  Google Scholar 

  71. Falk RH, Comenzo RL, Skinner M (1997) The systemic amyloidoses. N Engl J Med 337(13):898–909

    Article  CAS  PubMed  Google Scholar 

  72. Rubinow A, Skinner M, Cohen AS (1981) Digoxin sensitivity in amyloid cardiomyopathy. Circulation 63(6):1285–1288

    Article  CAS  PubMed  Google Scholar 

  73. Badar T, D’Souza A, Hari P. Recent advances in understanding and treating immunoglobulin light chain amyloidosis. F1000Res 2018; 7(F1000 Faculty Rev):1348

  74. Konstam MA, Rousseau MF, Kronenberg MW, Udelson JE, Melin J, Stewart D, Dolan N, Edens TR, Ahn S, Kinan D et al (1992) Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation 86(2):431–438

    Article  CAS  PubMed  Google Scholar 

  75. Groenning BA, Nilsson JC, Sondergaard L, Fritz-Hansen T, Larsson HB, Hildebrandt PR (2000) Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 36(7):2072–2080

    Article  CAS  PubMed  Google Scholar 

  76. Solomon SD, Foster E, Bourgoun M, Shah A, Viloria E, Brown MW, Hall WJ, Pfeffer MA, Moss AJ, Investigators M-C (2010) Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy. Circulation 122(10):985–992

    Article  PubMed  Google Scholar 

  77. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Plante-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH III, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB (2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379(1):11–21

    Article  CAS  PubMed  Google Scholar 

  78. Wood H (2018) FDA approves patisiran to treat hereditary transthyretin amyloidosis. Nat Rev Neurol 14(10):570

    PubMed  Google Scholar 

  79. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH III, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, BW ME, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T (2018) Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 379(1):22–31

    Article  CAS  PubMed  Google Scholar 

  80. Keam SJ (2018) Inotersen: first global approval. Drugs 78(13):1371–1376

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Angelos G. Rigopoulos and Muhammad Ali contributed equally to this work.

Authors and Affiliations

  1. Mid-German Heart Center, Department of Internal Medicine III (KIM-III), Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle, Ernst-Grube-Strasse 40, D-06120, Halle (Saale), Germany

    Angelos G. Rigopoulos, Muhammad Ali, Elena Abate, Abdel-Rahman Torky, Marios Matiakis, Mammad Mammadov, Hannes Melnyk, Alexander Vogt & Michel Noutsias

  2. Preventive Cardiology and Rehabilitation Unit, DSB 29, S. Gennaro dei Poveri Hospital, 80136, Naples, Italy

    Renato de Vecchis

  3. Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200, Berlin, Germany

    Boris Bigalke

  4. Department of Radiology, University Hospital Halle, Martin-Luther-University Halle, Ernst-Grube-Strasse 40, D-06120, Halle (Saale), Germany

    Walter Wohlgemuth

  5. Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61, Palaeo Faliro, Athens, Greece

    Sophie Mavrogeni

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  1. Angelos G. Rigopoulos
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Correspondence to Michel Noutsias.

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Conflict of interest

MN has received grants by the Deutsche Forschungsgemeinschaft through the Sonderforschungsbereich Transregio 19 “Inflammatory Cardiomyopathy” (SFB TR19) to MN (TP B2) and to CT (TP B5); and by the University Hospital Giessen and Marburg Foundation Grant “T cell functionality” (UKGM 10/2009). MN has been consultant to the IKDT (Institute for Cardiac Diagnosis and Therapy GmbH, Berlin) 2004–2008, and has received honoraria for presentations and/or participated in advisory boards from AstraZeneca, Bayer, Fresenius, Miltenyi Biotech, Novartis, Pfizer, and Zoll. AR has received honoraria for presentations from AstraZeneca. MA has received honoraria for presentations from AstraZeneca.

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Rigopoulos, A.G., Ali, M., Abate, E. et al. Advances in the diagnosis and treatment of transthyretin amyloidosis with cardiac involvement. Heart Fail Rev 24, 521–533 (2019). https://doi.org/10.1007/s10741-019-09776-3

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