European Journal of Heart Failure (2022) 24, 2367–2373 SHORT REPORT doi:10.1002/ejhf.2658 Frequency of hereditary transthyretin amyloidosis among elderly patients with transthyretin cardiomyopathy Alba Maestro-Benedicto1,2,3†, Paula Vela1†, Fernando de Frutos1, Nerea Mora1, Antonia Pomares1, Emiliano Gonzalez-Vioque1, Ana Briceño1, Eva Cabrera1, Marta Cobo-Marcos1, Fernando Dominguez1,4, Esther Gonzalez-Lopez1, Javier Segovia1, Enrique Lara-Pezzi4, and Pablo Garcia-Pavia1,4,5,6* 1 HeartFailure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, CIBERCV, Madrid, Spain; 2 IIB Sant Pau, Barcelona, Spain; 3 Heart Failure and Transplant Unit, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 4 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 5 Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain; and 6 Universidad Autónoma de Madrid, Madrid, Spain Received 14 April 2022; revised 4 August 2022; accepted 13 August 2022 ; online publish-ahead-of-print 11 September 2022 Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a cause of heart failure in the elderly. Although wild-type transthyretin amyloidosis is the most frequent form of ATTR-CM found in the elderly, hereditary transthyretin amyloidosis (ATTRv) can also occur. We sought to determine the prevalence of ATTRv among elderly ATTR-CM patients, identify predictors of ATTRv and evaluate the clinical consequences of positive genetic testing in this population. ..................................................................................................................................................................... Methods Prevalence of ATTRv in elderly ATTR-CM patients (≥70 years) was assessed in a cohort of 300 consecutive ATTR-CM and results patients (median age 78 years at diagnosis, 82% ≥70 years, 16% female, 99% Caucasian). ATTRv was diagnosed in 35 (12%; 95% confidence interval [CI] 3.1–8.8) and 13 (5.3%; 95% CI 5.6–26.7) patients in the overall cohort and in those ≥70 years, respectively. Prevalence of ATTRv among elderly female patients with ATTR-CM was 13% (95% CI 2.1–23.5). Univariate analysis identified female sex (odds ratio [OR] 3.66; 95% CI 1.13–11.85; p = 0.03), black ancestry (OR 46.31; 95% CI 3.52–Inf; p = 0.005), eye symptoms (OR 6.64; 95% CI 1.20–36.73; p = 0.03) and polyneuropathy (OR 10.05; 95% CI 3.09–32.64; p < 0.001) as the only factors associated with ATTRv in this population. Diagnosis of ATTRv in elderly ATTR-CM patients allowed initiation of transthyretin-specific drug treatment in 5 individuals, genetic screening in 33 relatives from 13 families, and identification of 9 ATTRv asymptomatic carriers. ..................................................................................................................................................................... Conclusions Hereditary transthyretin amyloidosis is present in a substantial number of ATTR-CM patients aged ≥70 years. Identification of ATTRv in elderly patients with ATTR-CM has clinical meaningful therapeutic and diagnostic implications. These results support routine genetic testing in patients with ATTR-CM regardless of age. .......................................................................................................... Keywords Amyloidosis • Transthyretin • Genetic testing • Elderly • Age *Corresponding author. Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, 28222 Madrid, Spain. Tel: + 34 91 1917297, Fax: +34 91 1917718, Email: pablo.garciap@uam.es † Co-first authors. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 2368 A. Maestro-Benedicto et al. patients. Data were analysed using STATA version 15.0 (StataCorp, Introduction ........................................................................................................................................................................ College Station, TX, USA). Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progres- sive heart disease caused by the extracellular deposition of transthyretin (TTR) amyloid fibrils, either in its hereditary (ATTRv) Results or wild-type (ATTRwt) form.1 During the study period, 342 patients were evaluated for Diagnosis of the hereditary nature of ATTR-CM allows genetic ATTR-CM. A total of 42 patients had to be excluded accord- counselling, permits familial screening (facilitating early diagnosis of ing to pre-specified criteria (Figure 1). Therefore, the final study relatives) and, if polyneuropathy is present, it enables treatment cohort comprised 300 subjects. Characteristics are presented in with certain TTR-specific drugs.1 Table 1. A total of 203 patients (67.7%) had been referred from Unfortunately, ATTR-CM is frequently assumed to be of other centres; 237 patients (79%) were referred by cardiologists wild-type origin and TTR genetic testing is not performed when while 63 (21%) were referred by other specialties (online sup- ATTR-CM is diagnosed in elderly individuals.2 plementary Table S1 and Figure S1). Eighty-two (40.4% of those With these considerations, we sought to determine the preva- referred) had not undergone genetic testing at the referral centre lence of ATTRv among elderly ATTR-CM patients, identify predic- and this proportion increased with age (Figure 2). tors of ATTRv and evaluate the clinical consequences of ATTRv Genetic testing revealed a pathogenic TTR variant in 35 patients diagnosis in this population. (12%). The most common genetic variant was Va142Ile (14, 40%), followed by Val50Met (9, 26%). The proportion of ATTRv patients decreased with age, despite ATTRv cases were found in all age Methods intervals (Figure 3). This was a retrospective analysis of consecutive ATTR-CM patients As expected, ATTRwt patients were older at diagnosis (79 evaluated at Hospital Universitario Puerta de Hierro (Madrid, Spain) [IQR 74–84] vs. 66 [IQR 58–75] years; p < 0.001) and were between December 2008 and November 2021. The study complies less frequently female (13% vs. 34%; p = 0.001). ATTRv had with the Helsinki Declaration and was approved by the institution’s more neurological symptoms (60% vs. 15%; p < 0.001) and ethics committee. higher estimated glomerular filtration rate (70.8 ± 19.4 vs. The diagnosis of ATTR-CM was established based on demonstration 60.1 ± 19.0 ml/min/1.73 m2 ; p = 0.002). Of note, electrocar- of TTR amyloid deposits on endomyocardial biopsy or by cardiac diographic and echocardiographic parameters and N-terminal uptake grade 2 or 3 on scintigraphy associated with suggestive findings on echocardiogram or cardiac magnetic resonance and no evidence pro-brain natriuretic peptide (NT-proBNP) levels did not differ of monoclonal protein.1 TTR genetic testing was performed by Sanger between groups. sequencing during evaluation at our centre or previously at referring centres. Other rare hereditary amyloidosis-associated genes were not evaluated. Elderly patients Patients in whom genetic testing was performed because of neu- A total of 279 (82%) ATTR-CM patients ≥70 years underwent rological disease or following ATTRv diagnosis in a relative were evaluation at our centre during the inclusion period; 33 patients excluded. were excluded according to pre-specified criteria. Therefore, the Clinical data were extracted from medical records and age ≥70 years final elderly cohort comprised 246 patients (online supplementary was used to define the elderly cohort. Figure S2). Characteristics are presented in Table 2. Among them, Clinical implications evaluated included: (i) initiation of specific 13 patients (5.3%; 95% CI 3.1–8.8%) had ATTRv (Figure 3). The therapies as a consequence of ATTRv diagnosis, (ii) number of relatives eldest ATTRv patient diagnosed was a 93-year-old Caucasian who underwent predictive genetic testing, and (iii) relatives diagnosed as ATTRv genetic carriers. female with the Val142Ile variant. Prevalence of ATTRv in elderly Genetic testing policy in relatives of ATTRv patients is to offer female patients was 13% (95% CI 5.6–26.7%). Distribution of genetic screening in adult relatives when the result of genetic screening ATTRv by age and sex is shown in online supplementary Figure S3. would have a clinical impact. This includes knowing genetic status for Univariate predictors of ATTRv in ATTR-CM elderly patients reproductive counselling and for professional advice in certain jobs included female sex, African ancestry, polyneuropathy, and eye where developing polyneuropathy/cardiomyopathy could be a limiting symptoms (Table 3). factor. If this is not the case, in general we recommend genetic screening around the age of 40 to discharge non-carriers and avoid unnecessary follow-up, although this varies depending on the type of Implications of ATTRv diagnosis variant (in case of early-onset Val50Met, we recommend screening in elderly patients around 20 years old). All patients diagnosed with ATTRv received genetic counseling. Moreover, diagnosis of ATTRv allowed initiation of tafamidis in five Statistical analyses subjects who had subsequent demonstration of polyneuropathy Continuous variables were reported as mean ± standard deviation, (tafamidis could not be prescribed for ATTR-CM at that time). or median and interquartile range (IQR). Categorical variables were Furthermore, cascade genetic testing was performed in 33 relatives reported as number and percentage. Logistic regression univariate from 13 families leading to identification of nine asymptomatic analysis was used to identify factors associated with ATTRv in elderly ATTRv carriers. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. ATTRv in elderly patients with ATTR-CM 2369 Figure 1 Flow-chart of study participants. ATTR-CM, transthyretin amyloid cardiomyopathy; EMB, endomyocardial biopsy. Discussion neurological manifestations and the incomplete penetrance and ................................................................................. late disease onset of certain ATTRv variants that preclude iden- This study describes the prevalence of ATTRv among a predom- tification of familial presentation. In fact, in our study, 40% of inantly Caucasian cohort of elderly patients with ATTR-CM. We elderly ATTR-CM patients referred from other centres had not found that in 5.3% of elderly ATTR-CM patients the condition had undergone genetic testing at origin. a genetic origin. Moreover, we showed that diagnosing ATTRv in In our study, one in 20 elderly ATTR-CM patients and one in 10 elderly individuals has important clinical consequences both for elderly females had ATTRv despite being diagnosed at ≥70 years patients and their families. Furthermore, we did not find any car- old. diac parameter to be associated with ATTRv and identified female The sex imbalance found in our study is consistent with previ- sex, black ancestry, eye symptoms and polyneuropathy as the only ous reports where ATTR-CM is predominantly identified in men, factors associated with ATTRv in this population. particularly ATTRwt. Although still understudied, the lower preva- Transthyretin amyloid cardiomyopathy, once thought to be a rare lence of ATTR-CM in women has been related to several factors, disease, is nowadays recognized to be a frequent cause of heart such as potential cardioprotective effect of female sex and under- failure with preserved ejection fraction and degenerative aortic diagnosis due to smaller heart structures and lack of awareness.8 stenosis.3,4 Recognition of the contribution of ATTR-CM in these We compared our patients with patients included in the THAOS clinical settings combined with advances in cardiac imaging and the international registry;9 European patients were younger than the appearance of specific therapies have led to a substantial increase American patients and than the patients included in our study. This in the number of ATTR-CM patients currently diagnosed.5,6 could be explained by the fact that most European participants Unfortunately, increased awareness has also led to emerging had ATTRv (91.1%), in contrast to US patients (51.5%) and ours problems in ATTR-CM diagnosis that include lack of exclusion (12%). Val30Met was the most common genetic variant in Europe of light-chain (AL) amyloidosis in patients with cardiac uptake in THAOS (80.7%), whereas in our study and in the US it was on scintigraphy, incomplete evaluations that do not include single Val142Ile (40% and 45.3%, respectively). Cardiomyopathy was an photon emission computed tomography and lack of genetic testing inclusion criterion in our study, which was present in almost all in elderly individuals.2,7 the American patients included in THAOS but only in one third The latter is a pitfall that has been favoured in non-endemic of the European patients in the registry. No relevant differences regions by the lower frequency of ATTRv compared to ATTRwt, in echocardiographic parameters were observed between patients the wrong perception that ATTRv invariably presents with included in THAOS and those included in our study. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2370 A. Maestro-Benedicto et al. Table 1 Baseline clinical characteristics Total Hereditary Wild-type p-value (n = 300) ATTR-CM (n = 35) ATTR-CM (n = 265) ........................................................................................................................................... Baseline characteristics Female sex, n (%) 47 (15.7) 12 (34.3) 35 (13.2) 0.001 Race, n (%) 0.003 Caucasian 297 (99.0) 33 (94.3) 262 (99.6) Black 3 (1.0) 2 (5.7) 1 (0.4) Age at diagnosis, years, median (IQR) 78 (72–84) 66 (58–75) 79 (74–84) <0.001 ATTRv genotype (n = 35), n (%) Val50Met 9 (25.7) Val142Ile 14 (40.0) Glu109Gln 1 (2.9) Glu109Lys 5 (14.3) Ser43Asn 3 (8.6) Thr60Ala 1 (2.9) Val142del 2 (5.7) Type of diagnosis, n (%) 0.99 Invasive 86 (28.7) 10 (28.6) 76 (28.7) Non-invasive 214 (71.3) 25 (71.4) 189 (71.3) Diagnostic era, n (%) 0.776 <2015 32 (10.7) 4 (11.4) 28 (10.6) 2016–2021 268 (89.3) 31 (88.6) 237 (89.4) Onset symptoms, n (%) 0.354 Dyspnoea 191 (63.7) 23 (65.7) 168 (63.4) Peripheral oedema 12 (4.0) 0 (0.0) 12 (4.5) Chest pain 8 (2.7) 1 (2.9) 7 (2.6) Palpitations 14 (4.7) 3 (8.6) 11 (4.2) Syncope 19 (6.3) 3 (8.6) 16 (6.0) Incidental finding 43 (14.3) 4 (11.4) 39 (14.7) Other 13 (4.3) 1 (2.9) 12 (4.5) Polyneuropathy, n (%) 61 (20.3) 21 (60.0) 40 (15.1) <0.001 Carpal tunnel syndrome, n (%) 116 (38.7) 16 (45.7) 100 (37.7) 0.362 History of embolism, n (%) 27 (9.0) 4 (11.4) 23 (8.7) 0.54 Atrial fibrillation, n (%) 188 (62.7) 12 (34.3) 176 (66.4) <0.001 Hypertension, n (%) 196 (65.3) 15 (42.9) 181 (68.3) 0.003 Coronary artery disease, n (%) 47 (15.7) 0 (0.0) 47 (17.7) 0.002 Pacemaker, n (%) 40 (13.3) 4 (11.4) 36 (13.6) 1 Chronic kidney disease (stage ≥3A), n (%) 141 (47.0) 9 (25.7) 132 (49.8) 0.007 Baseline blood tests eGFR, ml/min/1.73 m2 , mean ± SD 61.3 ± 19.3 70.8 ± 19.4 60.1 ± 19.0 0.002 NT-proBNP, pg/ml, median (IQR) 2400 (982–441) 2558 (959–5236) 2344 (991–4258) 0.54 Troponin I, μg/L, median (IQR) 0.06 (0.03–0.11) 0.04 (0.02–0.12) 0.06 (0.03–0.10) 0.45 Baseline ECG, n (%) 1st degree AV block 58 (19.3) 7 (20.0) 51 (19.3) 0.92 LBBB 50 (19.0) 6 (17.1) 44 (16.6) 0.95 RBBB (n = 297) 49 (16.3) 4 (11.4) 45 (17.0) 0.69 Baseline echocardiography Interventricular wall thickness, mm, mean ± SD 18.0 ± 3.5 18.8 ± 3.7 17.9 ± 3.4 0.16 End-diastolic left ventricular diameter, mm, mean ± SD 42.9 ± 6.5 40.9 ± 6.6 43.2 ± 6.5 0.06 Left ventricular ejection fraction, %, mean ± SD 53.6 ± 11.3 55.0 ± 9.9 53.7 ± 11.5 0.51 Global longitudinal strain, −% (n = 217), mean ± SD 12.4 ± 4.3 12.5 ± 3.7 12.4 ± 4.4 0.93 Left atrial diameter, mm, mean ± SD 44.6 ± 6.9 42.4 ± 7.0 44.8 ± 6.9 0.08 Aortic stenosis (at least moderate), n (%) 10 (3.3) 0 (0.0) 10 (3.8) 0.61 Pericardial effusion, n (%) 52 (17.5) 9 (25.7) 43 (16.4) 0.17 ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRv, hereditary transthyretin amyloidosis; AV, atrioventricular; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; IQR, interquartile range; LBBB, left bundle branch block; NT-proBNP, N-terminal pro-brain natiuretic peptide; RBBB, right bundle branch block; SD, standard deviation. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. ATTRv in elderly patients with ATTR-CM 2371 Figure 2 Proportion of referred patients with and without transthyretin genetic testing performed at referral centres. Figure 3 Prevalence of hereditary transthyretin amyloidosis (ATTRv) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) according to age. Interestingly, the Val142Ile variant was the commonest variant neurological evaluation and initiation of TTR-specific drugs. In our .................................... found in our study despite patients included in our cohort were study, five patients initiated tafamidis thanks to ATTRv diagnosis as predominantly Caucasian. Our study adds to previous reports that tafamidis was not reimbursed for ATTR-CM in Spain at that time. also showed higher than expected prevalence of the Val142Ile Nevertheless, even if tafamidis had been available for ATTR-CM, variant potentially suggesting that it could be an underestimated other therapeutic alternatives that are only available for ATTRv variant among Caucasian ATTR-CM patients.10 patients with polyneuropathy could have been considered.1 Transthyretin genetic testing is simple and cheap nowadays The positive implications of diagnosing ATTRv extend to rela- and limiting genetic evaluation in ATTR-CM patients could have tives that can benefit from cascade screening and early diagnosis. important negative effects if ATTRv is not appropriately diagnosed. In our study, nine ATTRv genetic carriers were diagnosed and At the patient level, identification of ATTRv enables genetic will undergo periodic surveillance allowing identification of disease counselling and better delineation of prognosis as ATTRv has worse manifestations at early stages where specific treatments are more prognosis than ATTRwt,11 but also could lead to a more precise effective.12 © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 2372 A. Maestro-Benedicto et al. Table 2 Baseline characteristics of elderly transthyretin amyloid cardiomyopathy patients (n = 246) Total Hereditary Wild-type p-value (n = 246) ATTR-CM (n = 13) ATTR-CM (n = 233) ........................................................................................................................................... Baseline characteristics Female sex, n (%) 39 (15.9) 5 (38.5) 34 (14.6) 0.022 Race, n (%) <0.001 Caucasian 244 (99.2) 11 (84.6) 233 (100) Black 2 (0.8) 2 (15.4) 0 (0.0) Age at diagnosis, years, median (IQR) 80 (76–85) 79 (73–82) 80 (76–85) 0.26 ATTRv genotype (n = 35), n (%) Val50Met 3 (23.1) Val142Ile 10 (76.9) Type of diagnosis, n (%) 1.00 Invasive 65 (26.4) 3 (23.1) 62 (26.6) Non-invasive 181 (73.6) 10 (76.9) 171 (73.4) Diagnosis era, n (%) 1.00 <2015 25 (10.2) 1 (7.7) 24 (10.3) 2016–2021 221 (89.8) 12 (92.3) 209 (89.7) Onset symptoms, n (%) 0.802 Dyspnoea 191 (63.7) 23 (65.7) 168 (63.4) Peripheral oedema 12 (4.0) 0 12 (4.5) Chest pain 8 (2.7) 1 (2.9) 7 (2.6) Palpitations 14 (4.7) 3 (8.6) 11 (4.2) Syncope 19 (6.3) 3 (8.6) 16 (6.0) Incidental finding 43 (14.3) 4 (11.4) 39 (14.7) Other 13 (4.3) 1 (2.9) 12 (4.5) Polyneuropathy, n (%) 40 (16.3) 8 (61.5) 32 (13.7) <0.001 Carpal tunnel syndrome, n (%) 87 (35.4) 7 (53.9) 80 (34.3) 0.152 History of embolism, n (%) 22 (8.9) 3 (23.1) 19 (8.2) 0.07 Atrial fibrillation, n (%) 166 (67.5) 7 (53.9) 159 (68.2) 0.281 Hypertension, n (%) 172 (69.9) 8 (61.5) 164 (70.4) 0.498 Coronary artery disease, n (%) 40 (16.3) 0 40 (17.8) 0.135 Pacemaker, n (%) 40 (22.5) 2 (22.2) 38 (22.5) 1 Chronic kidney disease (stage ≥3A), n (%) 126 (51.2) 5 (38.5) 121 (51.9) 0.402 Baseline blood tests eGFR, ml/min/1.73 m2 , mean ± SD 58.6 ± 18.1 63.1 ± 20.3 58.3 ± 17.9 0.357 NT-proBNP, pg/ml, median (IQR) 2592 (1020–4498) 4794 (1650–9524) 2544 (1020–4413) 0.104 Conventional troponin I (μg/L), median (IQR) 0.06 (0.03–0.11) 0.08 (0.04–0.19) 0.06 (0.03–0.10) 0.45 Baseline ECG, n (%) 1st degree AV block 42 (17.1%) 1 (7.7%) 41 (17.6%) 0.70 LBBB 41 (16.7%) 3 (23.1%) 38 (16.3) 0.27 RBBB 44 (17.9%) 1 (7.7%) 43 (18.5%) 0.29 Baseline echocardiogram Interventricular wall thickness, mm, mean ± SD 17.9 ± 3.4 18.7 ± 3.0 17.9 ± 3.4 0.40 End-diastolic left ventricular diameter, mm, mean ± SD 42.7 ± 6.4 40.5 ± 5.8 42.8 ± 6.5 0.21 Left ventricular ejection fraction, %, mean ± SD 54.2 ± 11.5 57.1 ± 6.8 54.0 ± 11.7 0.35 Global longitudinal strain, −% (n = 173), mean ± SD 12.3 ± 4.4 11.2 ± 2.5 12.3 ± 4.5 0.44 Left atrial diameter, mm, mean ± SD 44.7 ± 6.4 41.1 ± 6.9 44.9 ± 6.4 0.06 Aortic stenosis (at least moderate), n (%) 10 (3.3) 0 (0.0) 10 (3.8) 0.61 Pericardial effusion, n (%) 52 (17.5) 9 (25.7) 43 (16.4) 0.17 ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRv, hereditary transthyretin amyloidosis; AV, atrioventricular; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; IQR, interquartile range; LBBB, left bundle branch block; NT-proBNP, N-terminal pro-brain natiuretic peptide; RBBB, right bundle branch block; SD, standard deviation. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. ATTRv in elderly patients with ATTR-CM 2373 Supplementary Information ........................................................................................................................................................... Table 3 Factors associated with hereditary transthyretin amyloidosis in elderly patients with Additional supporting information may be found online in the transthyretin amyloid cardiomyopathy Supporting Information section at the end of the article. Univariate analysis ..................................... Odds 95% CI p-value Funding Ratio ................................................................ This study has been funded by Instituto de Salud Carlos III (ISCIII) Age at diagnosis 0.95 0.85–1.05 0.29 through the projects ‘PI18/0765 & PI20/01379’ (co-funded by (per year) European Regional Development Fund/European Social Fund ‘A Female sex 3.66 1.13–11.85 0.03 way to make Europe’/‘Investing in your future’). AMB receives grant Black ancestry 46.31 3.52–Inf 0.005 support by ISCIII (CM20/002209). The CNIC is supported by the Hypertension 0.67 0.21–2.13 0.50 ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Diabetes 1.37 0.41–4.63 0.61 grant (CEX2020-001041-S). Carpal tunnel syndrome 2.23 0.73–6.86 0.16 Conflict of interest: none declared. Lumbar spinal stenosis 0.51 0.06–4.01 0.52 Coronary artery disease 0.27 0.00–1.66 0.19 Polyneuropathy 10.05 3.09–32.64 <0.001 References Dysautonomia 1.14 0.30–4.29 0.85 1. Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, et al. 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J Am Coll Cardiol. 2016;68:161–72. patients in our cohort precludes generalization to other cohorts 10. Cappelli F, Frusconi S, Bergesio F, Grifoni E, Fabbri A, Giuliani C, et al. with higher proportion of black individuals (where 3–4% carry The Val142Ile transthyretin cardiac amyloidosis: not only an Afro-American pathogenic variant? A single-centre Italian experience. J Cardiovasc Med (Hager- the Val142Ile variant).13 However, even with a predominantly Cau- stown). 2016;17:122–5. casian cohort, the prevalence of ATTRv found was considerable. 11. Rapezzi C, Elliott P, Damy T, Nativi-Nicolau J, Berk JL, Velazquez EJ, et al. Efficacy of tafamidis in patients with hereditary and wild-type transthyretin amyloid cardiomyopathy: further analyses from ATTR-ACT. JACC Heart Fail. 2021;9:115–23. Conclusions 12. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al.; ATTR-ACT Study Investigators. Tafamidis treat- Prevalence of ATTRv among predominantly Caucasian elderly ment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. patients with ATTR-CM was 5.3% and its diagnosis had meaningful 2018;379:1007–16. 13. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, et al. clinical implications. These results support routine genetic testing The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl in ATTR-CM regardless of age. J Med. 2015;372:21–9. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.