Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Thibaud Damy, Arnt V Kristen, Ole B Suhr, Mathew S Maurer, Violaine Planté-Bordeneuve, Ching-Ray Yu, Moh-Lim Ong, Teresa Coelho, Claudio Rapezzi, THAOS Investigators, Thibaud Damy, Arnt V Kristen, Ole B Suhr, Mathew S Maurer, Violaine Planté-Bordeneuve, Ching-Ray Yu, Moh-Lim Ong, Teresa Coelho, Claudio Rapezzi, THAOS Investigators

Abstract

Aims: Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).

Methods and results: THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n = 210), compared with a mixed (n = 298), phenotype: higher median (Q1-Q3) interventricular septal thickness [18 (16-21) vs. 16 (13-20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both).

Conclusion: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease.

Trial registration: ClinicalTrials.gov: NCT00628745.

Keywords: ATTR amyloidosis; Cardiomyopathy; Registry.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1
Figure 1
Subject phenotypes and most common genotype in subjects enrolled in THAOS in continental Western Europe. Data are from all European countries included in THAOS. Shown are: the total number of subjects from each country in THAOS, the proportions of each phenotype, and the most common mutation in each country (with its percentage of all subjects in that country). Not shown are: Belgium, three subjects with cardiac + neurologic phenotype (genotypes: Val30Met, Glu54Leu, and Glu74Leu); and Cyprus, one subject with neurologic phenotype (genotype: Val30Met). Note that the most common form of ATTR amyloidosis in Germany and Italy was ATTRwt (41.6% and 34.2% of all subjects, respectively).
Figure 2
Figure 2
A Kaplan–Meier survival curve by genotype for subject death. The 95% Hall–Wellner bands and Cox proportional hazards model are adjusted by age and sex (χ2 log rank: P < 0.0001). Survival curves are from enrolment in THAOS.
Figure 3
Figure 3
A Kaplan–Meier survival curve by phenotype for subject death. The 95% Hall–Wellner bands and Cox proportional hazards model are adjusted by age and sex (χ2 log rank: P < 0.0001). Survival curves are from enrolment in THAOS.

References

    1. Plante-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011;10:1086–1097.
    1. Rapezzi C, Quarta CC, Riva L, Longhi S, Gallelli I, Lorenzini M, Ciliberti P, Biagini E, Salvi F, Branzi A. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 2010;7:398–408.
    1. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kuhl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–276.
    1. Buxbaum JN, Tagoe CE. The genetics of the amyloidoses. Annu Rev Med 2000;51:543–569.
    1. Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160–184.
    1. Rowczenio DM, Noor I, Gillmore JD, Lachmann HJ, Whelan C, Hawkins PN, Obici L, Westermark P, Grateau G, Wechalekar AD. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat 2014;35:E2403–E2412.
    1. Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952;75:408–427.
    1. Parman Y, Adams D, Obici L, Galan L, Guergueltcheva V, Suhr OB, Coelho T. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol 2016;29(Suppl 1):S3–S13.
    1. Carr AS, Pelayo-Negro AL, Evans MR, Laura M, Blake J, Stancanelli C, Iodice V, Wechalekar AD, Whelan CJ, Gillmore JD, Hawkins PN, Reilly MM. A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J Neurol Neurosurg Psychiatry 2016;87:620–627.
    1. 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. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34:520–528.
    1. Hornsten R, Pennlert J, Wiklund U, Lindqvist P, Jensen SM, Suhr OB. Heart complications in familial transthyretin amyloidosis: impact of age and gender. Amyloid 2010;17:63–68.
    1. Conceicao I, De Carvalho M. Clinical variability in type I familial amyloid polyneuropathy (Val30Met): comparison between late- and early-onset cases in Portugal. Muscle Nerve 2007;35:116–118.
    1. Zaros C, Genin E, Hellman U, Saporta MA, Languille L, Wadington-Cruz M, Suhr O, Misrahi M, Planté-Bordeneuve V. On the origin of the transthyretin Val30Met familial amyloid polyneuropathy. Ann Hum Genet 2008;72:478–484.
    1. Suhr OB, Lundgren E, Westermark P. One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. J Intern Med 2017;281:337–347.
    1. Castano A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 2015;20:163–178.
    1. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733–2779.
    1. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang C-C, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin K-P, Vita G, Attarian S, Planté-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH, 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. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379:11–21.
    1. 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 3rd, 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, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379:22–31.
    1. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington Cruz M, Kristen AV, Grogan DR, Witteles R, Damy T, Drachman B, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007–1016.
    1. Plante-Bordeneuve V, Suhr OB, Maurer MS, White B, Grogan DR, Coelho T. The transthyretin amyloidosis outcomes survey (THAOS) registry: design and methodology. Curr Med Res Opin 2013;29:77–84.
    1. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid 2015;22:171–174.
    1. Svendsen IH, Steensgaard-Hansen F, Nordvag BY. A clinical, echocardiographic and genetic characterization of a Danish kindred with familial amyloid transthyretin methionine 111 linked cardiomyopathy. Eur Heart J 1998;19:782–789.
    1. Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, Rowczenio D, Pflugfelder PW, Fox Z, Lachmann HJ, Wechalekar AD, Hawkins PN, Gillmore JD. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J 2012;33:1120–1127.
    1. Almeida MR, Hesse A, Steinmetz A, Maisch B, Altland K, Linke RP, Gawinowicz MA, Saraiva MJ. Transthyretin Leu 68 in a form of cardiac amyloidosis. Basic Res Cardiol 1991;86:567–571.
    1. 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. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol 2016;68:161–172.
    1. Reilly MM, Staunton H, Harding AE. Familial amyloid polyneuropathy (TTR ala 60) in North West Ireland: a clinical, genetic, and epidemiological study. J Neurol Neurosurg Psychiatry 1995;59:45–49.
    1. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol 2016;68:1014–1020.
    1. Suhr OB, Svendsen IH, Andersson R, Danielsson A, Holmgren G, Ranlov PJ. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Intern Med 2003;254:225–235.
    1. Damy T, Costes B, Hagège AA, Donal E, Eicher J-C, Slama M, Guellich A, Rappeneau S, Gueffet J-P, Logeart D, Planté-Bordeneuve V, Bouvaist H, Huttin O, Mulak G, Dubois-Randé J-L, Goossens M, Canoui-Poitrine F, Buxbaum JN. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J 2016;37:1826–1834.
    1. Cariou E, Bennani Smires Y, Victor G, Robin G, Ribes D, Pascal P, Petermann A, Fournier P, Faguer S, Roncalli J, Rousseau H, Chauveau D, Carrie D, Berry I, Galinier M, Lairez O; Toulouse Amyloidosis Research Network Collaborators. Diagnostic score for the detection of cardiac amyloidosis in patients with left ventricular hypertrophy and impact on prognosis. Amyloid 2017;24:101–109.
    1. 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. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36:2585–2594.
    1. Hellman U, Lundgren HE, Westermark P, Stafberg C, Nahi H, Tachlinski S, Guggi M, Flogegard M, Hamid M, Escher SA, Suhr OB. A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family. Eur J Med Genet 2015;58:211–215.
    1. Bauer R, Dikow N, Brauer A, Kreuter M, Buss S, Evers C, Rocken C, Schnabel PA, Hinderhofer K, Ehlermann P, Katus HA, Kristen AV. The “Wagshurst study”: P.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. Amyloid 2014;21:267–275.
    1. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, Salvi F, Ciliberti P, Pastorelli F, Biagini E, Coccolo F, Cooke RM, Bacchi-Reggiani L, Sangiorgi D, Ferlini A, Cavo M, Zamagni E, Fonte ML, Palladini G, Salinaro F, Musca F, Obici L, Branzi A, Perlini S. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120:1203–1212.
    1. Rapezzi C, Riva L, Quarta CC, Perugini E, Salvi F, Longhi S, Ciliberti P, Pastorelli F, Biagini E, Leone O, Cooke RM, Bacchi-Reggiani L, Ferlini A, Cavo M, Merlini G, Perlini S, Pasquali S, Branzi A. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 2008;15:40–48.
    1. Arvidsson S, Pilebro B, Westermark P, Lindqvist P, Suhr OB. Amyloid cardiomyopathy in hereditary transthyretin V30M amyloidosis–impact of sex and amyloid fibril composition. PLoS One 2015;10:e0143456..
    1. Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc 1988;63:552–564.
    1. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113–122.
    1. Damy T, Maurer MS, Rapezzi C, Plante-Bordeneuve V, Karayal ON, Mundayat R, Suhr OB, Kristen AV. Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy. Open Heart 2016;3:e000289..
    1. Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB, Damy T. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis–report from the Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One 2017;12:e0173086..
    1. Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR, Furtado E, Barroso E, Daniel J, Samuel D, Adam R, Karam V, Poterucha J, Lewis D, Ferraz-Neto BH, Cruz MW, Munar-Ques M, Fabregat J, Ikeda S, Ando Y, Heaton N, Otto G, Suhr O. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation 2015;99:1847–1854.
    1. Suhr OB, Larsson M, Ericzon BG, Wilczek HE. Survival after transplantation in patients with mutations other than Val30Met: extracts from the FAP World Transplant Registry. Transplantation 2016;100:373–381.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe