Gentile et al. Orphanet Journal of Orphanet Journal of Rare Diseases (2023) 18:350 https://doi.org/10.1186/s13023-023-02962-5 Rare Diseases RESEARCH Open Access A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS) Luca Gentile1* , Teresa Coelho2, Angela Dispenzieri3, Isabel Conceição4, Márcia Waddington‑Cruz5, Arnt Kristen6, Jonas Wixner7, Igor Diemberger8,9, Juan Gonzalez‑Moreno10, Eve Cariou11, Mathew S. Maurer12, Violaine Planté‑Bordeneuve13, Pablo Garcia‑Pavia14,15, Ivailo Tournev16,17, Jose Gonzalez‑Costello18, Alejandra Gonzalez Duarte19,20, Martha Grogan21, Anna Mazzeo1, Doug Chapman22, Pritam Gupta23, Oliver Glass22 and Leslie Amass22 on behalf of the THAOS investigators Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life‑threatening disease resulting from the deposition of variant or wild‑type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tis‑ sues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild‑type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15‑year data from the THAOS registry. Results This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14‑year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14‑year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predomi‑ nantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5). Conclusions This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for mul‑ tidisciplinary management of ATTR amyloidosis. Trial registration ClinicalTrials.gov Identifier: NCT00628745. Keywords Amyloidosis, Cardiomyopathy, Polyneuropathy, Transthyretin, Registry *Correspondence: Luca Gentile luca.gentile@unime.it Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 2 of 12 Introduction The analysis population comprised all patients enrolled Transthyretin amyloidosis (ATTR amyloidosis) is a pro- in THAOS (data cutoff date: August 1, 2022). The defi- gressive, multisystemic, life-threatening disease char- nitions of symptomatic status, asymptomatic status, acterized by deposits of amyloid fibrils in the peripheral and those with missing symptomatic status have been nerves, heart, and other tissues and organs, resulting in described previously [10]. Demographics, clinical char- polyneuropathy, cardiomyopathy, or a mix of both neu- acteristics, and patient-reported outcomes collected rologic and cardiac manifestations [1–3]. ATTR amy- at enrollment were analyzed in the overall cohort of loidosis may be caused by one of over 130 pathogenic symptomatic patients and by the following genotype mutations that destabilize the TTR protein (hereditary subgroups: ATTRwt amyloidosis, V30M (p.V50M) with ATTR amyloidosis [ATTRv amyloidosis]) or the accu- early-onset disease (age ≤ 50 years, based on age at diag- mulation of non-mutated TTR protein (wild-type ATTR nosis), V30M with late-onset disease (age > 50 years), and amyloidosis [ATTRwt amyloidosis]) [3, 4]. The pheno- non-V30M. typic presentation of ATTRv amyloidosis is clinically Phenotype at enrollment was analyzed in symptomatic heterogeneous and can be predominantly neurologic, patients by region as previously described [10]. Patients predominantly cardiac, or mixed phenotype, depend- were classified by phenotype based on the following ing on the particular TTR variant and other factors [2, definitions: Predominantly cardiac phenotype included 5]. ATTRwt amyloidosis most often presents as cardio- patients with abnormal electrocardiogram (ECG) due myopathy [1]. If left untreated, median survival estimates to rhythm disturbance, heart failure, or dyspnea and in patients with ATTR amyloidosis range from 2 to 10 no more than mild neurologic or gastrointestinal (GI) years, depending on genotype and other factors [1, 2, 6]. symptoms (excluding erectile dysfunction, constipa- Diagnosing ATTR amyloidosis can be difficult due to low tion, and carpal tunnel); cardiac symptoms did not need disease awareness, indeterminate family history, and the to be ongoing at a given visit to be included for pheno- heterogeneity of clinical presentation that can overlap typing, but symptoms had to be definitely ATTR amy- with more common diseases [2, 6, 7]. Better clinical char- loidosis related. Predominantly neurologic phenotype acterization of the disease may lead to earlier identifica- included patients with neurologic or GI symptoms of tion and intervention, which is associated with improved any severity and without abnormal ECG due to rhythm outcomes [8]. disturbance, heart failure, or dyspnea; neurologic and GI Established in 2007, the Transthyretin Amyloidosis symptoms had to be ongoing and definitely ATTR amy- Outcomes Survey (THAOS) is an ongoing, global, lon- loidosis related. A modified Polyneuropathy Disability gitudinal, observational survey of patients with ATTR (mPND) score ≥ I was considered a neurologic symptom amyloidosis, including both hereditary and wild-type in this analysis, whereas it was not in prior analyses [10]. disease, and asymptomatic carriers with TTR mutations Mixed phenotype included patients with abnormal ECG [9]. THAOS collects multinational, longitudinal data on due to rhythm disturbance, heart failure, or dyspnea, and the natural history of the disease from a large, diverse neurologic or GI symptoms of any severity, but who did patient population to help inform the characterization not satisfy criteria for a predominantly cardiac or pre- of ATTR amyloidosis and improve disease diagnosis and dominantly neurologic phenotype. Unknown phenotype patient management. This analysis provides an annual included all other symptomatic patients who did not update [10] of the characteristics of patients with ATTR meet any of the above criteria for either predominantly amyloidosis (both ATTRv and ATTRwt) and asympto- cardiac, predominantly neurologic, or mixed phenotypes. matic gene carriers at the time of their enrollment into All patients with ATTRwt amyloidosis were classified as THAOS, providing a global overview of THAOS data predominantly cardiac at enrollment unless they had any since its inception 15 years ago. neurologic symptoms definitely related to ATTR amy- loidosis, in which case they were classified as having a mixed phenotype. Methods The categorization of symptoms and their manifesta- Study design and patient population tions have been described [10]. Demographics collected The study design and eligibility criteria of THAOS have at enrollment were also summarized for the asympto- been described [11]. All study sites received ethical or matic carriers overall and by genotype category (V30M institutional review board approval prior to patient and non-V30M). enrollment, and all patients provided written informed consent. The Good Pharmacoepidemiology Practice Assessments guidelines and the principles of the Declaration of Hel- Assessments have been described in detail [10]. Briefly, sinki were duly followed for this study. a patient’s ability to perform normal life activities and G entile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 3 of 12 need for assistance was assessed in symptomatic patients in THAOS patients (48.0%) as was reported in the pre- using the Karnofsky Performance Status Scale Score. vious year’s report [10], followed by ATTRwt amyloido- Neurologic impairment was measured in symptomatic sis (25.2%) and V122l (p.V142I) (6.0%) (Additional file 1: patients using the derived Neuropathy Impairment Score Table S1). Among the symptomatic patients, V30M (early in the Lower Limbs (NIS-LL) and mPND scores. Cardiac or late onset) was most commonly enrolled in Europe measures included select echocardiographic measures, (54.2%), South America (79.5%), and Japan (75.4%), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) wild-type disease was most commonly enrolled in North concentration, and New York Heart Association (NYHA) America (59.5%) (Fig.  2a; Additional file  2: Table  S2). class. Quality of Life (QoL) was assessed using the EQ- The non-V30M variant was more common (even more 5D-3L and the Norfolk Quality of Life – Diabetic Neu- prevalent than the wild type) in some individual coun- ropathy questionnaire. tries (Mexico, Bulgaria, Denmark, Israel, Italy, Roma- nia, Turkey, Malaysia and Taiwan), although the overall Statistical analyses trend showed that V30M was the predominant geno- This was a descriptive analysis. Continuous data are type. Among the symptomatic patients with a predomi- presented as mean (standard deviation [SD]) or median nantly cardiac phenotype, the non-Val30Met subgroup (10th, 90th percentile), and categorical data are presented accounted for more than half the patients in Asia (55.3%) as count (percentage). and South America (52.6%) (Fig. 2b). The non-Val30Met subgroup also accounted for 90.2% of the patients with a Results predominantly neurologic phenotype in North America, Demographics and genotype whereas, for other regions (South America, Europe and There were 6368 patients from 85 study sites and 23 Asia), the V30M genotype (early or late onset) was more countries enrolled in THAOS at the data cutoff date prevalent (Fig. 2c). The ATTRwt genotype accounted for (Fig.  1). This included 4428 symptomatic patients and almost half (49.4%) of the symptomatic patients with a 1707 asymptomatic gene carriers. There were 233 wild- mixed phenotype in North America (Fig. 2d). type patients who, despite having all symptoms assessed, Symptomatic patients were predominantly male across did not meet the definition for the symptomatic set [10]. all genotype subgroups (Table 1). Overall, the mean age at V30M remained the most prevalent genotype enrolled symptom onset was 56.6 years and was higher in patients Europe (N = 4032) North America (N = 1594) Belgium (n = 9) Bulgaria (n = 129) Canada (n = 27) Cyprus (n = 1) Mexico (n = 106) Denmark (n = 44) United States (n = 1461) France (n = 414) Germany (n = 423) Israel (n = 43) Italy (n = 407) Netherlands (n = 45) Portugal (n = 1665) Romania (n = 22) Spain (n = 565) Sweden (n = 257) Turkey (n = 8) Asia (N = 274) Japan (n = 155) Malaysia (n = 23) Republic of Korea (n = 88) Taiwan (n = 8) South America (N = 468) Argentina (n = 100) Brazil (n = 368) Fig. 1 Geographic distribution of all patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS) Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 4 of 12 A. All patients (n = 4428) B. Predominantly cardiac (n = 1413) 60 80 60 40 40 20 20 0 0 Asia Europe North South Asia Europe North South America America America America C. Predominantly neurologic (n = 1712) D. Mixed (n = 1085) 50 75 40 30 50 20 25 10 0 0 Asia Europe North South Asia Europe North South America America America America ATTRwt amyloidosis V30M early onset V30M late onset Non−V30M Fig. 2 Regional distribution of genotype subgroups in symptomatic patients. The proportion of patients with each genotype shown by region in a the overall population of symptomatic patients and in patients with b predominantly cardiac, c predominantly neurologic, and d mixed phenotypes. ATTRwt amyloidosis = wild‑type transthyretin amyloidosis with ATTRwt amyloidosis compared with the other In contrast to symptomatic patients, the asymptomatic genotype subgroups. Mean time from symptom onset carriers had a higher proportion of females overall (58.5%), to diagnosis was 4.0 years in all symptomatic patients as did the V30M subgroup (61.4%) (Table 2). The mean age and ranged from 2.8 years in the early-onset V30M sub- at enrollment was 41.9 years overall and was higher in the group to 4.6 years in the ATTRwt amyloidosis subgroup. non-V30M subgroup compared with V30M asymptomatic V30M remained the most prevalent genotype among the gene carriers. symptomatic patients in South America (79.5%), Europe (54.2%), and Asia (including Japan; 47.8%). The majority of these patients had early-onset disease in each of these regions (Fig. 2a; Additional file 2: Table S2). % of patients % of patients % of patients % of patients G entile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 5 of 12 Table 1 Demographics of symptomatic patients according to genotype category Overall (n = 4428) ATTRwt V30M early onset V30M late onset Non-V30M amyloidosis (n = 1082) (n = 670) (n = 1264) (n = 1410) Male, n (%) 3137 (70.8) 1315 (93.3) 565 (52.2) 433 (64.6) 822 (65.0) Race/ethnicitya, n (%) White 2450 (77.2) 1141 (94.1) 263 (68.3) 382 (83.2) 663 (59.5) African descent 310 (9.8) 38 (3.1) 33 (8.6) 18 (3.9) 221 (19.8) American Hispanic 17 (0.5) 1 (0.1) 10 (2.6) 1 (0.2) 5 (0.4) Latino American 136 (4.3) 8 (0.7) 22 (5.7) 4 (0.9) 102 (9.1) Asian 245 (7.7) 18 (1.5) 56 (14.5) 53 (11.5) 118 (10.6) Other 14 (0.4) 6 (0.5) 1 (0.3) 1 (0.2) 6 (0.5) Age at enrollment (years), mean (SD) 62.5 (17.22) 77.9 (7.14) 40.6 (9.44) 68.6 (7.94) 60.9 (13.22) Age at onset of ATTR amyloidosis symptoms (years) n = 4421 n = 1409 n = 1082 n = 670 n = 1259 Mean (SD) 56.6 (17.93) 72.3 (9.73) 33.8 (7.19) 63.3 (8.14) 55.0 (13.88) Time from symptom onset to diagnosis (years) n = 4069 n = 1337 n = 993 n = 596 n = 1142 Mean (SD) 4.0 (5.96) 4.6 (6.73) 2.8 (4.74) 3.7 (3.96) 4.4 (6.61) Follow‑up t imeb (years), mean (SD) 3.9 (3.20) 2.3 (1.94) 6.8 (3.29) 4.1 (3.03) 3.2 (2.61) V30M early onset and late onset n based on all patients with available data for disease diagnosis Symptom onset was the date of first occurrence of symptom(s) reported as definitely related to ATTR amyloidosis ATTR amyloidosis transthyretin amyloidosis, ATTRwt amyloidosis wild-type transthyretin amyloidosis, SD standard deviation a Denominator for race/ethnicity is the total of non-missing records b Follow-up time is based on all patients, from enrollment to last observation Table 2 Demographics of asymptomatic gene carriers according to genotype category Overall (n = 1707) V30M (n = 1272) Non-V30M (n = 435) Male, n (%) 708 (41.5) 491 (38.6) 217 (49.9) Race/ethnicitya, n (%) Caucasian 670 (80.2) 407 (88.3) 263 (70.3) African descent 86 (10.3) 29 (6.3) 57 (15.2) American Hispanic 9 (1.1) 5 (1.1) 4 (1.1) Latino American 38 (4.6) 10 (2.2) 28 (7.5) Asian 28 (3.4) 7 (1.5) 21 (5.6) Other 4 (0.5) 3 (0.7) 1 (0.3) Age at enrollment (years), mean (SD) 41.9 (15.51) 39.4 (14.57) 49.3 (15.81) SD standard deviation a Denominator for race/ethnicity is the total of non-missing records Distribution of phenotypes at enrollment in symptomatic non-V30M (34.4.%) subgroups (Fig. 3a; Additional file 2: patients Table  S2). In South America, predominantly neurologic The overall phenotype distribution for symptomatic was the most prevalent phenotype at enrollment overall patients at enrollment showed, in respect to last-year’s (65.6%) as well as in the V30M (early and late onset) sub- analysis, an increase in the proportion of mixed pheno- group (76.7%). The proportion of symptomatic patients type from 16.6% [10] to 24.5%. The predominantly car- with predominantly neurologic phenotype in Europe diac (31.9%), predominantly neurologic (38.7%), and was 48.7% (Fig. 3a; Additional file 2: Table S2). In symp- unknown (4.9%) phenotypes accounted for the remain- tomatic patients with ATTRwt amyloidosis, 84.5% had ing symptomatic patients (Additional file  2: Table  S2). a predominantly cardiac phenotype in North America, In North America, the majority of symptomatic patients which was higher than in the other regions (Europe, had a predominantly cardiac phenotype overall (63.9%) South America and Asia; Fig.  3b). In Europe, the pre- as well as in the ATTRwt amyloidosis (84.5%) and dominantly neurologic phenotype was found in 72.2% of Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 6 of 12 A. All patients (n = 4428) B. ATTRwt amyloidosis (n = 1410) 100 100 75 75 50 50 25 25 0 0 Asia Europe North South Asia Europe North South America America America America C. V30M early onset (n = 1082) D. V30M late onset (n = 670) 100 100 75 75 50 50 25 25 0 0 Asia Europe North South Asia Europe North South America America America America E. Non–V30M (n = 1264) 100 Phenotype Predominantly cardiac Predominantly neurologic 75 Mixed No phenotype 50 25 0 Asia Europe North South America America Fig. 3 Regional distribution of phenotype at enrollment in symptomatic patients. The proportion of patients with each phenotype shown by region in a the overall population of symptomatic patients and by genotype category, b ATTRwt amyloidosis, c V30M early onset, d V30M late onset, e non‑V30M. ATTRwt amyloidosis = wild‑type transthyretin amyloidosis % of patients % of patients % of patients % of patients % of patients Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 7 of 12 patients in the V30M (early or late onset) subgroup, and 100 in 40.6% of patients in the non-V30M subgroup (Fig. 3c, d, e; Additional file  2: Table  S2). The mixed phenotype was more prevalent in Asian countries (excluding Japan) 75 with an overall 40.6% of symptomatic patients (Addi- tional file 2: Table S2). The V30M late-onset subgroup had a greater propor- tion of mixed phenotypes versus the early-onset sub- 50 group (30.6% vs. 13.8%) (Additional file  2: Table  S2). The V30M late-onset predominantly cardiac phenotype showed a decrease in proportion among the symptomatic 25 patients as compared to last year (4.3% vs. 1.4% [10]). The proportion of symptomatic patients with ATTRwt amyloidosis with a mixed phenotype at enrollment also 0 showed a jump from 9.8% as observed in the previous iac gic ed pe year [10] to 23.9% (Additional file 2: table S2), but as dis- ard rolo Mix oty tly c n neu phe cussed further below this result is due to a change in the minan ly o o inant N definition of mixed phenotype in THAOS. Pred dom Pre The non-Val30Met subgroup was prevalent among ATTRwt amyloidosis (n = 1410) symptomatic patients with a mixed phenotype (36.3%; V30M early onset (n = 1082) Fig.  4). The V30M early onset group accounted for half V30M late onset (n = 670) of the symptomatic patients with a predominantly neuro- Non–V30M (n = 1264) logic phenotype (Fig. 4). Fig. 4 Distribution of phenotype at enrollment in symptomatic patients according to genotype category. The proportions of patients with each phenotype are shown by genotype. ATTRwt Clinical characteristics at enrollment in symptomatic amyloidosis = wild‑type transthyretin amyloidosis patients The neurologic impairment was more prominent in the V30M (including early and late onset) and non-V30M with V30M (86.0% vs. 28.4%; Fig.  5a, b, c). Among the subgroups as indicated by the derived NIS-LL score non-Val30Met subgroup, sensory neuropathy and cardiac (Additional file  3: Table  S3). Patients with late-onset disorders were more frequent (60.1% and 58.8% respec- V30M had the highest neurologic impairment. Greater tively) as compared with the other symptoms (Fig. 5d). cardiac involvement in patients with ATTRwt amyloido- sis compared with V30M ATTRv amyloidosis was sug- Cardiac characteristics at enrollment in symptomatic gested by greater left ventricular septum thickness and patients with a predominantly cardiac or mixed phenotype decreased left ventricular ejection fraction (Additional Heart failure was present in 87.0% of the ATTRwt amy- file 3: Table S3). Quality of life, measured by EQ-5D-3L loidosis subgroup as compared to 72.3% of the ATTRv index score and visual analog scale, was comparable amyloidosis subgroup in the subset of patients with a between the ATTRwt, V30M, and non-V30M subgroups; predominantly cardiac or mixed phenotype (Table  3). however, higher corresponding Norfolk Quality of Life – A similar greater proportion of patients with abnormal Diabetic Neuropathy questionnaire scores were observed ECG, atrial fibrillation/flutter, pacemaker/implantable for the V30M late-onset and non-V30M subgroups. cardioverter-defibrillator, and higher values of the cardiac As observed in last year’s data cutoff [10], sensory neu- biomarkers (Troponin T, NT-proBNP) were observed in ropathy (54.6%), cardiac disorder (55.4%), and autonomic the ATTRwt amyloidosis subgroup as compared to the neuropathy (45.1%) were the most common symptoms ATTRv amyloidosis subgroup. corresponding to the symptomatic patients overall. GI manifestations were more common in the V30M (early or late onset) subgroup (59.9%) as compared to the ATTRwt Neurologic characteristics at enrollment in symptomatic amyloidosis subgroup (3.5%; Fig. 5a, b, c). Similar trends patients with a predominantly neurologic or mixed were also observed for autonomic neuropathy and sen- phenotype sory neuropathy with more patients in the V30M (early Most patients with a predominantly neurologic or mixed or late onset) subgroup having these symptom categories. phenotype had a score of I (56.9%) or II (19.1%) on the Conversely, cardiac disorders were more frequent among mPND (Additional file 4: Table S4). Patients with V30M patients with ATTRwt amyloidosis as compared to those late-onset disease had greater walking impairment than % of patients Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 8 of 12 A. ATTRwt amyloidosis (n = 1410) B. V30M early onset (n = 1082) 86 82.2 80 80 73.8 67.8 60 60 40 40 35.8 27.4 30.1 21.8 20 14.3 15.9 20 2.8 3.5 0 0 C. V30M late onset (n = 670) D. Non–V30M (n = 1264) 84.3 80 80 60.1 60.1 60 60 58.8 51.8 47.2 45.1 39 41.5 40 35.2 40 33.1 28.9 20 20 0 0 Motor neuropathy Autonomic neuropathy Cardiac disorder Sensory neuropathy Gastrointestinal manifestations Other Fig. 5 Symptom categories at enrollment in symptomatic patients according to genotype category. V30M early onset and late onset n based on all patients with available data for disease diagnosis. ATTRwt amyloidosis = wild‑type transthyretin amyloidosis those with V30M early-onset disease (mPND > II, 24.7% genotype subgroups (ATTRwt amyloidosis, early- and vs. 9.1%). late-onset V30M, non-V30M), the highest rate of pre- dominantly cardiologic patients was always found in Discussion North America. The reasons for the differences observed This 15-year global overview of > 6000 patients with are unknown: it has been suggested that they could be ATTR amyloidosis and asymptomatic gene carriers is the related to differences in the age of the populations, the largest analysis of ATTR amyloidosis to date. The find- use of scintigraphy imaging techniques in clinical prac- ings presented in this study are largely consistent with tice, reliance on and/or expertise in the performance and the data from the last annual assessment [10]. interpretation of endomyocardial biopsy specimens, and In this study, V30M and the associated predominantly specialty of THAOS investigators (e.g., neurologist vs. neurologic phenotype continued to be more prevalent cardiologist) [12]. However, they might also reflect the in Europe, South America, and Japan, whereas wild-type true differences in the prevalence of the condition, sug- disease and the predominantly cardiologic phenotype gesting a possible role of ambient or socioeconomic fac- were most common in North America. Notably, for all tors in increasing the predisposition to cardiac disease. % of patients % of patients % of patients % of patients G entile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 9 of 12 Table 3 Cardiac characteristics at enrollment in symptomatic patients with a predominantly cardiac or mixed phenotype ATTRwt amyloidosis (n = 1410) ATTRv amyloidosis (n = 3017) Heart failure, n (%) 1227 (87.0) 787 (72.3) NYHA functional classa, n (%) I 126 (10.5) 111 (14.2) II 729 (60.9) 392 (50.2) III 315 (26.3) 246 (31.5) IV 27 (2.3) 32 (4.1) Abnormal ECG, n (%) 1170 (83.0) 670 (61.6) Atrial fibrillation/flutter, n (%) 509 (36.1) 114 (10.5) Pacemaker implanted, n (%) 216 (15.3) 65 (6.0) ICD implanted, n (%) 73 (5.2) 28 (2.6) NT‑proBNP (pg/mL) n = 707 n = 255 Median (10th, 90th percentiles) 2146.0 (526.0, 6312.0) 1791.0 (229.0, 6627.0) Troponin I (ng/mL) n = 112 n = 97 Median (10th, 90th percentiles) 0.1 (0.0, 0.3) 0.1 (0.0, 0.5) Troponin T (ng/mL) n = 270 n = 164 Median (10th, 90th percentiles) 0.0 (0.0, 0.1) 0.0 (0.0, 0.2) ATTRwt amyloidosis wild-type transthyretin amyloidosis, ECG electrocardiogram, ICD implantable cardioverter-defibrillator, NP-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, SD standard deviation a Denominator for NYHA functional class is the total of non-missing records Finally, non-V30M genotypes were highly represented of time (a mean of 2.8 years after symptom onset). This in some individual European, American, and Asian delay could result from the rarity of ATTR amyloidosis, countries (e.g., Mexico, Bulgaria, Denmark, Israel, Italy, the wide spectrum of possible symptoms, and the likely Romania, Turkey, Malaysia, and Taiwan). presence of confounding comorbidity (especially for Male predominance among symptomatic patients was patients with ATTRwt amyloidosis). observed in this analysis for all subgroups. However, in Compared with last year’s analysis, the proportion of the early-onset V30M subgroup, this difference was less predominantly neurologic patients remained stable (from pronounced (males, 52.2%; females, 47.8%), consistent 40.1 to 38.7%). However, we observed a considerable with the findings of a Japanese nationwide survey [13]. In overall reduction of predominantly cardiac phenotype contrast, a higher proportion of asymptomatic carriers (from 40.7 to 31.9%) and an increase in mixed phenotype were female than male, as suggested in previous studies (from 16.6 to 24.5%). This difference was mainly influ- that recorded lower disease penetrance in females, espe- enced by a change in the definition of the mixed pheno- cially those associated with specific genotypes or cardiac type in THAOS, namely that an mPND score ≥ I is now manifestation of ATTR amyloidosis [14–18]. considered a definitely ATTR amyloidosis–related neuro- As expected, patients with ATTRwt amyloidosis were logic symptom, whereas before it was not. As a result of the oldest at symptom onset (mean age, 72.3 years), this modification, among the four subgroups of patients which occurred almost 10 years after the late-onset (ATTRwt, early- and late-onset V30M, non-V30M), V30M subgroup and > 15 years after the non-V30M sub- phenotype distribution varied primarily in the ATTRwt group. Patients with early-onset V30M were the youngest subgroup. In these patients, mixed phenotype went from at disease onset (mean age, 33.8 years) and received an 9.8% as observed in the last year [10] to 23.9%, with a ATTR amyloidosis diagnosis earlier than the other geno- decrease of predominantly cardiac phenotype (from 89 to type subgroups (0.9–1.7 years before). This last finding 76.1%). The global geographic distribution of the mixed may contribute to the fact that these patients presented phenotype illustrated it was more prevalent in Asia for with a significant minor grade of walking impairment the ATTRwt and V30M subgroups, and in South Amer- (9.1% of patients with mPND score ≥ 2) as compared to ica for the non-V30M subgroup. the other genotypes (20.4% in ATTRwt, 22.7% in late- THAOS has notable strengths in that the registry rep- onset V30M, 18.4% in non-V30M). It should also be resents a large, geographically diverse group of countries noted that, despite everything, patients with early-onset and study sites worldwide, and provides a more accurate V30M received a diagnosis after a significant amount global picture of the current state of ATTR amyloidosis. Gentile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 10 of 12 The large study population of > 6000 patients is a fur- Munoz Beamud, Hospital Juan Ramon Jimenez, Huelva, Spain; David Slosky, ther strength of this analysis. Study limitations include Vanderbilt University School of Medicine, Nashville, TN, USA; Mazen Hanna, Cleveland Clinic Foundation, Cleveland, OH, USA; Miriam Freimer, The Ohio potential differences among study sites in data collection University College of Medicine, Columbus, OH, USA; Hans Nienhuis, University methods, and that the inclusion criteria for THAOS have Medical Center Groningen, Groningen, The Netherlands; Henning Moelgaard, evolved over time. In addition, temporal bias may have Aarhus University Hospital, Skejby, Aarhus, Denmark; David Adams, CHU de Bicetre, Cedex, France; Edward Miller, Smilow Cancer Hospital, New Haven, played a role in these findings, as the number and spe- CT, USA; Amir Dori, Sheba Medical Center, Ramat Gan, Israel; Rayomand Press, cialties of study sites increased and changed over time, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Jocelyn Inamo, which may have been the greatest influential factor in Chu De Fort De France, Fort de France, France; Calogero Lino Cirami, Azienda Ospedaliero ‑ Universitaria di Careggi, Firenze, Italy; Josep Maria Campistol the patterns observed. Referral bias may have impacted Plana, Institut Clinic de Nefrologia i Urologia, ICNU, Hospital Clinic i Provincial phenotype categorization since cardiac centers may not de Barcelona, Barcelona, Spain; Michele Emdin, Fondazione Toscana Gabriele conduct comprehensive neurologic assessments and vice Monasterio Per La Ricerca Medica E Di Sanita Pubblica, Pisa, Italy; Dianna Quan, UC Denver, Aurora, CO, USA; Scott Hummel, University of Michigan, Ann Arbor, versa. This could have resulted in an under-representa- MI, USA; Edileide de Barros Correia, Instituto Dante Pazzanese De Cardiologia, tion of the mixed phenotype. In addition, recruitment Sao Paulo, Brazil; Ronald Witteles, Stanford University School of Medicine, rates with study sites may vary over time, and registry Stanford, CA, USA; Cheng Yin Tan, University Malaya Medical Centre, Kuala Lumpur, Malaysia; Olga Azevedo, Centro Hospitalar Do Alto Ave, Epe, Guima‑ data, by nature, are not always complete and are limited raes, Portugal; Sanjiv Shah, Northwestern University, Chicago, IL, USA; Daniel by the data imputed. Lastly, management of ATTR amy- Lenihan, Washington University School of Medicine, St. Louis, MO, USA; Sorina loidosis has evolved over the last few decades and clinical Badelita, Institutul De Cardiologie, Bucuresti, Romania; Srinivas Murali, Wexford Health and Wellness Pavillion, Pittsburgh, PA, USA; Sasa Zivkovic, University awareness has increased given the emergence of disease- of Pittsburgh Medical Center, Pittsburgh, PA, USA; Jose Nativi Nicolau, The modifying treatments; therefore, patients enrolled in the University of Utah Health Sciences Center, Salt Lake City, UT, USA; Jose Tallaj, later years of THAOS likely received more comprehen- University of Alabama, Birmingham, AL, USA; Nowell Fine, University of Alberta Foothills Medical Centre, Calgary, Canada; Carsten Tschoepe, Charite Campus sive assessments than those enrolled in the earlier era. Rudolf‑Virchow‑Klinikum, Berlin, Germany; Roberto Fernandéz Torrón, Hospital Universitario Donostia, Gipuzkoa, San Sebastian, Spain; Laura Obici, Centro per Conclusion lo Studio e la Cura delle Amiloidosi Sistemiche, Pavia, Italy; Michael Polydefkis, Johns Hopkins Hospital, Baltimore, MD, USA; Stephen Gottlieb, University This analysis of > 6000 patients and asymptomatic TTR of Maryland, Baltimore, MD, USA; James Tauras, Montefiore Medical Center, gene carriers from THAOS continues to underscore the Jack D. Weiler Hospital, Bronx, NY, USA; Hector Ventura, John Ochsner Heart & heterogeneity and increasing awareness of ATTR amyloi- Vascular Institute, New Orleans, LA, USA; Christopher Mueller, Medical College of Wisconsin, Milwaukee, WI, USA; Robert Brunkhorst, University Hospital of dosis. The mixed phenotype and multisystemic involve- RWTH Aachen, Aachen, Germany; Felix Darstein, Johann‑Gutenberg‑Univer‑ ment are increasingly recognized, highlighting the need sität, Mainz, Germany; Jeeyoung Oh, Konkuk University Medical Center, Seoul, for a consistent, multidisciplinary approach to the man- Republic of Korea; Tessa Marburger, Oregon Health and Science University, Portland, OR, USA; Alberta Warner, VA Greater Los Angeles Healthcare System, agement of ATTR amyloidosis. Los Angeles, CA, USA; Johan Van Cleemput, Afdeling Klinische Cardiologie, O&N I, Leuven, Belgium; Diego Delgado, Toronto General Hospital, Toronto, Supplementary Information Canada; Valeria Lujan Salutto, Instituto De Investigaciones Medicas, Ciudad Autonoma De Buenos Aires, Argentina; Yesim Parman, Istanbul University, The online version contains supplementary material available at https://d oi. Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey; org/1 0. 1186/s 13023‑ 023‑ 02962‑5. Chi‑Chao Chao, National Taiwan University Hospital, Taipei, Taiwan; Nitasha Sarswat, University of Chicago Medical Center, Chicago, IL, USA; David Steidley, Additional file 1: Table S1 Most frequent genotypes recorded at enroll‑ Mayo Clinic Arizona, Phoenix, AZ, USA; Jeffrey Ralph, University of California, ment in the overall population Department of Neurology, San Francisco, LA, USA; William Cotts, Advocate Christ Medical Centre, Oak Lawn, IL, USA; James Hoffman, University of Miami Additional file 2: Table S2 Distribution of phenotype at enrollment in Hospital & Clinics, Miami, FL, USA; Marcelo Rugiero, Hospital Italiano de Buenos symptomatic patients according to genotype category Aires, Buenos Aires, Argentina; Sonoko Misawa, Chiba University Hospital, Additional file 3: Table S3 Clinical characteristics and patient‑reported Chiba‑shi, Japan; Jose Luis Munoz Blanco, Hospital Gregorio Marañón, outcomes at enrollment in symptomatic patients according to genotype Madrid, Spain; Lucia Galan Davila, Hospital Clinico San Carlos, Madrid, Spain; category Menachem Sadeh, Wolfson Medical Center, Holon, Israel; Jin Luo, Temple University School of Medicine, Philadelphia, PA, USA; Theodoros Kyriakides, Additional file 4: Table S4 Neurologic characteristics at enrollment Cyprus Institute of Neurology and Genetics, NICOSIA, Cyprus; Annabel Wang, in symptomatic patients with a predominantly neurologic or mixed University of California, Irvine, Orange, CA, USA; Horacio Kaufmann, NYU Medi‑ phenotype cal Center, New York, NY, USA.We thank all THAOS patients and investigators for their important contributions to this study. Manuscript formatting support was provided by Emily Balevich, PhD, of Engage Scientific Solutions and was Acknowledgements funded by Pfizer; no contribution was made to editorial content. Additional THAOS investigators contributing to this analysis: Anna Hüsing‑ Kabar, Universitatsklinikum Muenster, Transplant Hepatology, Muenster, Author contributions Germany; Brian Drachman, University of Pennsylvania, Perelman Center for LG, TC, AD, IC, MW‑C, AK, JW, ID, JG‑M, EC, MSM, VP‑B, PG‑P, IT, JG‑C, AGD, MG, Advanced Medicine, Philadelphia, PA, USA; Fabio Adrian Barroso, FLENI, Ciudad and AM contributed data to the analysis as a participating study site in the Autonoma de Buenos Aires, Argentina; Mitsuharu Ueda, Kumamoto University, clinical study. LG, DC, PG, OG, and LA contributed to the analysis of the data. Kumamoto, Japan; Eun‑Seok Jeon, Samsung Medical Center, Sungkyunk‑ All authors contributed to the study design, interpretation of data, and prepa‑ wan University School of Medicine, Seoul, Republic of Korea; Marco Luigetti, ration, review, and approval of the manuscript. Fondazione Policlinico Gemelli, Universita Cattolica del Sacro Cuore, Roma, Italy; Yoshiki Sekijima, Shinshu University School of Medicine, Matsumoto, Japan; Anna Mazzeo, AOU Policlinico G. Martino, Messina, Italy; Francisco G entile et al. Orphanet Journal of Rare Diseases (2023) 18:350 Page 11 of 12 Funding Brazil. 6 Department of Cardiology, Angiology, Respiratory Medicine, Medi‑ The THAOS registry and this analysis were sponsored by Pfizer. Pfizer contrib‑ cal University of Heidelberg, Heidelberg, Germany. 7 Department of Public uted to the study design and management and collection of data. In their role Health and Clinical Medicine, Umeå University, Umeå, Sweden. 8 Department as authors, employees of Pfizer were involved in the interpretation of data, of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy. preparation, review, and approval of the manuscript and the decision to sub‑ 9 Cardiology Unit, IRCCS Policlinico di S. Orsola, Bologna, Italy. 10 Hospital Son mit for publication, along with their co‑authors. The study sponsors approved Llatzer, Palma de Mallorca, Spain. 11 Department of Cardiology, University Hos‑ the manuscript from an intellectual property perspective but had no right to pital Rangueil, Toulouse, France. 12 Columbia University College of Physicians veto the publication. and Surgeons, New York, NY, USA. 13 Hopital Henri Mondor, East Paris‑Créteil University, Assistance Publique‑Hopitaux de Paris, Créteil, France. 14 Hos‑ Availability of data and materials pital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain. Upon request, and subject to review, Pfizer will provide the data that support 15 Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. 16 Clinic the findings of this study. Subject to certain criteria, conditions and excep‑ of Nervous Diseases, Department of Neurology, UMBAL Aleksandrovska, tions, Pfizer may also provide access to the related individual de‑identified Medical University‑Sofia, Sofia, Bulgaria. 17 Department of Cognitive Science, participant data. See https://w ww. pfizer.c om/ scienc e/ clini cal‑ trials/t rial‑ data‑ New Bulgarian University, Sofia, Bulgaria. 18 Hospital Universitari de Bellvitge, and‑ result s for more information. IDIBELL, CIBER‑CV, Barcelona, Spain. 19 NYU Langone School of Medicine, New York, NY, USA. 20 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. 21 Department of Cardiovascular Diseases, Mayo Declarations Clinic, Rochester, MN, USA. 22 Pfizer Inc, New York, NY, USA. 23 Pfizer Healthcare India Pvt Ltd, Chennai, India. Ethics approval and consent to participate All THAOS sites received ethical or institutional review board approval prior to Received: 11 May 2023 Accepted: 28 October 2023 patient enrollment, and each patient provided written informed consent. The study followed the Good Pharmacoepidemiology Practice guidelines and the principles of the Declaration of Helsinki. Consent for publication Not applicable. References 1. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Competing interests amyloid cardiomyopathy: JACC state‑of‑the‑art review. J Am Coll Cardiol. Luca Gentile reports travel grants from Kedrion and CSL Behring to attend 2019;73:2872–91. scientific meetings. Teresa Coelho reports serving as a medical advisor for 2. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline Pfizer and receiving funding for scientific meeting expenses (travel, accom‑ of transthyretin‑related hereditary amyloidosis for clinicians. 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