Detecting early cardiomyopathy in transthyretin variant carriers: reappraising the diagnostic value of Perugini Grade 1 radiotracer uptake on bone scintigraphy

Detecting early cardiomyopathy in transthyretin variant carriers: reappraising the diagnostic value of Perugini Grade 1 radiotracer uptake on bone scintigraphy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Detecting early cardiomyopathy in transthyretin variant carriers: reappraising the diagnostic value of Perugini Grade 1 radiotracer uptake on bone scintigraphy Hendrea Sanne Aletta Tingen, M Berends, A Tubben, P van der Meer, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6275795/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 May, 2025 Read the published version in European Journal of Nuclear Medicine and Molecular Imaging → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose To determine whether TTRv carriers with Perugini grade 1 cardiac radiotracer uptake on [ 99m Tc]Tc- hydroxydiphosphonate bone scintigraphy have or develop ATTR-CM. Methods This retrospective observational study was conducted at the Groningen Amyloidosis Centre of Expertise between April 2012 and June 2023. TTRv carriers with Perugini grade 1 uptake on bone scintigraphy were followed until to June 2024. Data on symptoms, biomarkers, imaging, and biopsies were collected. A descriptive analysis was performed to evaluate whether carriers met the diagnostic criteria for ATTR-CM or ‘probable ATTR-CM’ at baseline and follow-up. Results Out of 178 TTRv carriers in screening, 12 carriers had Perugini grade 1 cardiac radiotracer uptake on bone scintigraphy. At baseline, 2 carriers met the diagnostic criteria for ATTR-CM and 3 carriers met the criteria for probable ATTR-CM. Of the 7 carriers without (probable) ATTR-CM at baseline, 3 carriers were diagnosed with ATTR-CM during follow-up and 1 carrier developed probable ATTR-CM during follow-up. Three carriers showed signs of cardiomyopathy during follow-up, but did not meet the criteria for (probable) ATTR-CM. One of these cases may have been false-positive due to hydroxychloroquine use. Conclusion Our findings suggest that Perugini grade 1 cardiac radiotracer uptake is an early marker of ATTR-CM in TTRv carriers, potentially enabling earlier diagnosis and intervention. ATTRv screening ATTR-CM diagnosis early detection Figures Figure 1 Figure 2 Full Text Individuals with a pathogenic transthyretin gene variant ( TTRv ) are at risk for developing hereditary transthyretin (ATTRv) amyloidosis [1]. In this population, screening for ATTR cardiomyopathy (ATTR-CM), a common disease manifestation, is essential for the early detection of subclinical ATTR-CM and timely treatment initiation, which improves patient outcomes [2,3]. Bone scintigraphy has high accuracy for detecting ATTR-CM [4,5]. Its high accuracy and non-invasive nature make bone scintigraphy an attractive screening tool for ATTR-CM. Perugini grade 2 or 3 cardiac radiotracer uptake is diagnostic for ATTR-CM, provided there is no evidence for immunoglobulin light chain amyloidosis. In contrast, grade 1 uptake requires histological confirmation and additional findings on cardiac imaging to diagnose ATTR-CM [6]. However, in high-risk individuals such as TTRv carriers, it may represent an early indicator of ATTR-CM. We investigated whether TTRv carriers with Perugini grade 1 cardiac radiotracer uptake on [ 99m Tc]Tc- hydroxydiphosphonate bone scintigraphy have or develop ATTR-CM. The study aimed to determine if Perugini grade 1 could be considered diagnostic of early-stage ATTR-CM in TTRv carriers. This retrospective observational study included all TTRv carriers undergoing treatment or screening at the Groningen Amyloidosis Centre of Expertise (GrACE) between April 2012 and June 2023 and was approved by the ethical board of the University Medical Centre Groningen (registration number: 17471). As a part of the GrACE screening program for ATTR-CM, all TTRv carriers regularly underwent bone scintigraphy, performed 3 hours after administration of 450 to 750 MBq [ 99m Tc]Tc-hydroxydiphosphonate. Bone scintigraphy was performed on dedicated single photon emission computed tomography (SPECT)/CT systems (Symbia T2, Symbia T16 or Symbia Intevo, Siemens Healthineers, Erlangen, Germany) equipped with a low-energy high-resolution collimator. Anterior planar whole-body scans were scored according to the Perugini grading system and SPECT/CT scans were reviewed to confirm myocardial uptake [7]. For patients with Perugini grade 1 uptake on bone scintigraphy, data were collected from patient records until June 2024, including symptoms, cardiac biomarkers, abdominal fat tissue aspirates and tissue biopsies for amyloid detection, electrocardiography, echocardiography, cardiac magnetic resonance imaging (CMR), and bone scintigraphy. The first bone scintigraphy showing Perugini grade 1 uptake was considered the baseline scan. A descriptive analysis was performed to evaluate whether individuals met the diagnostic criteria for ATTR-CM, as outlined in the European Society of Cardiology (ESC) position paper, at baseline and follow-up [6]. TTRv carriers who did not meet the ESC diagnostic criteria were classified as having ‘probable ATTR-CM’ if they met the criteria previously used by Rapezzi et al. [8,9]. These criteria include increased wall thickness on echocardiography (end-diastolic interventricular septal and/or left ventricular posterior wall thickness ≥12 mm) and/or advanced atrioventricular block (greater than first-degree) or intraventricular conduction disturbances (bundle branch blocks/hemiblocks) on electrocardiography without an alternative explanation, combined with histologically confirmed amyloid in an extracardiac biopsy. A total of 178 TTRv carriers were screened between 2012 and 2023. Among them, 117 carriers had Perugini grade 0 (66%), 9 had grade 1 (5%), 21 had grade 2 (12%), and 31 had grade 3 (17%) cardiac radiotracer uptake on the first bone scintigraphy during screening. Notably, 3 of the 117 TTRv carriers with Perugini grade 0 uptake on their initial bone scintigraphy showed Perugini grade 1 uptake on a follow-up scan (figure 1). Clinical data were collected for the 12 TTRv carriers with Perugini grade 1 uptake on bone scintigraphy at any time during screening. Their TTR gene variants were p.(Val50Met) (n=7), p.(Glu109Lys) (n=2), and p.(Ser43Asn) (n=1), p.(Ile127Val) (n=1), and p.(Val114Ala) (n=1). Table 1 and figure 2 provide information on whether these TTR v carriers met the criteria for (probable) ATTR-CM at the baseline scan or during follow-up, along with relevant clinical parameters and details. Table 1: Fulfilment of criteria for (probable) ATTR-CM and clinical parameters in TTRv carriers with Perugini grade 1 cardiac radiotracer uptake Pt Study category TTRv First proof of amyloid in tissue Time point ATTR-CM Year Clinical parameters Treatment ESC echo and CMR criteria Perugini grade IVSt on echo (mm) LVPWt on echo (mm) Conduction disturbances as defined in main text NTproBNP (ng/L) Hs-cTnT (ng/L) 1 Diagnosis at baseline p.(Ile127Val) Baseline Fat aspirate B Diagnosis 2020 None Yes 1 14 12 No 1063 26 2 Diagnosis at baseline p.(Val114Ala) Baseline Fat aspirate B Diagnosis 2022 None Yes 1 12 12 No 71 12 3 Diagnosis during FU p.(Ser43Asn) Baseline Fat aspirate B Insufficient evidence 2017† St No 1 8 8 No 80 5 FU Diagnosis 2020 St, Si No 2 8 9 No 63 8 4 Diagnosis during FU p.(Val50Met) No amyloid B Insufficient evidence 2012 None No 1 13 10 No 30 10 FU Diagnosis 2016 None No 2 13 8 No 63 18 5 Diagnosis during FU p.(Val50Met) Baseline Fat aspirate B Insufficient evidence 2012 St No 1 11 10 No 247 16 FU Diagnosis 2014 St No 2 13 13 No 333 17 6 Probable ATTR-CM at baseline, diagnosis during FU p.(Glu109Lys) Baseline GI biopsy, fat aspirate B Probable 2012 St No 1 14 10 No 86 6 FU Diagnosis 2016 St, Si No 2 15 10 No 102 8 7 Probable ATTR-CM at baseline p.(Val50Met) Baseline Fat aspirate B Probable 2021† OLTx No 1 14 10 Yes 572 16 FU Probable 2022 OLTx No 1 14 10 Yes 544 19 8 Probable ATTR-CM at baseline p.(Val50Met). Baseline Fat aspirate B Probable 2012 None No 1 12 13 Yes 547 41 FU Probable 2015 None No 1 12 14 Yes 1547 91 9 Probable ATTR-CM during FU p.(Val50Met) During follow-up Fat aspirate B Insufficient evidence 2013 None No 1 10 10 No 105 12 FU Probable 2024 Si No 1 10 10 No 522 19 10 No diagnosis p.(Val50Met) No amyloid B Insufficient evidence 2020 None No 1 15 9 No 79 8 11‡ No diagnosis p.(Glu109Lys) During follow-up Fat aspirate B Insufficient evidence 2015† St No 1 8 8 No 623 <3 FU Insufficient evidence 2023 St No 1 8 10 No 433 9 12 No diagnosis p.(Val50Met) Baseline Nerve biopsy, fat aspirate B Insufficient evidence 2015 St No 1 11 10 No 54 9 FU Insufficient evidence 2022 St, Si No 1 9 11 No 87 11 Follow-up data are presented up to the time of diagnosis, although follow-up may have continued thereafter. For TTRv carriers with only a single bone scintigraphy, follow-up data from other tests are not included but may be available for assessment of cardiac status. FU = follow-up; Pt = patient; TTRv = transthyretin gene variant; B = baseline; ESC = European Society of Cardiology; CMR = cardiac magnetic resonance imaging; IVSt = inter ventricular septal thickness; NTproBNP = N-terminal pro b-type natriuretic peptide; hs-cTnT = high sensitivity cardiac troponin T; St = transthyretin stabilizer; Si = transthyretin gene silencer; OLTx = orthotopic liver transplantation; ATTR-CM = transthyretin amyloid cardiomyopathy; GI = gastro-intestinal; † = these carriers had a previous bone scintigraphy showing Perugini grade 0; ‡ = this carrier used hydroxychloroquine. At baseline, 2 out of 12 TTRv carriers met the ESC diagnostic criteria for ATTR-CM based on extracardiac biopsy and echocardiography. Three others were classified as having probable ATTR-CM at baseline. One of these carriers met the ESC diagnostic criteria after a follow-up of 3.5 years and the other 2 carriers showed worsening of cardiac parameters over follow-up periods of 4 and 12 years. Of the 7 carriers without (probable) ATTR-CM at baseline, 3 carriers were diagnosed with ATTR-CM, after a follow-up of 2, 2 and 4 years, based on Perugini grade 2 cardiac radiotracer uptake on bone scintigraphy. Of the remaining 4 carriers, 1 carrier developed probable ATTR-CM after a follow-up of 11 years, based on increased wall thickness on echocardiography and a positive fat tissue aspirate. Three carriers showed signs of cardiomyopathy during follow-up, but did not meet the criteria for ATTR-CM or probable ATTR-CM. These signs included abnormal gadolinium kinetics on CMR, reduced global longitudinal strain and increased interventricular septal thickness on echocardiography. In 1 of these carriers, bone scintigraphy results might have been false-positive due to the use of hydroxychloroquine [6]. Moreover, it is important to note that treatment for ATTRv neuropathy was initiated during follow-up for all 3 of these carriers, potentially slowing or even halting the progression of ATTR-CM. To our knowledge, this is the largest study to date that longitudinally evaluates whether TTRv carriers with Perugini grade 1 uptake on bone scintigraphy have or develop ATTR-CM. In 9 out of 12 TTRv carriers (75%), Perugini grade 1 cardiac radiotracer uptake was indicative of (probable) ATTR-CM or its development. In 2 out of 12 individuals (17%), signs of cardiac deterioration were observed during follow-up, but were insufficient to diagnose (probable) ATTR-CM. In the remaining patient, grade 1 uptake might have been false-positive due to hydroxychloroquine use [6]. Our data highlight that cardiac radiotracer uptake on bone scintigraphy is a dynamic phenomenon. In our cohort, 3 TTRv carriers initially showed no cardiac radiotracer uptake but later developed Perugini grade 1 uptake. Similarly, 4 carriers progressed from grade 1 to grade 2 uptake during follow-up. In line with our findings, Minutoli et al. previously reported a case series including 3 asymptomatic TTRv carriers who developed symptoms of ATTR-CM along with cardiac abnormalities, in whom Perugini grade 1 uptake preceded these changes [5]. Consistently, Rauf et al. showed that Perugini grade 1 uptake in ATTR-CM was associated with earlier disease stages compared to higher grades according to NT-proBNP levels, echocardiography and CMR [10]. In the context of these studies, our findings provide additional support that Perugini grade 1 uptake represents early-stage ATTR-CM in TTRv carriers. Moreover, previous studies have shown that Perugini grade 1 is not an infrequent finding in ATTR-CM as it is observed in 8% of patients with endomyocardial biopsy-confirmed ATTR-CM [4]. In addition, the specificity of a positive bone scintigraphy for cardiac amyloidosis is high, ranging from 97-99% depending on the non-(cardiac) amyloidosis controls chosen [4]. Rauf et al. reported that of 3354 patients referred for suspected or proven cardiac amyloidosis, 183 had Perugini grade 1 uptake on bone scintigraphy, with 182 diagnosed with cardiac amyloidosis and only 1 false positive [10]. Further supporting the notion that TTRv carriers with Perugini grade 1 uptake on bone scintigraphy should be considered as having early-stage ATTR-CM. Major limitations of our study are the absence of endomyocardial biopsies and incomplete echocardiographic and CMR data for some patients. Other limitations are the low number of patients with Perugini grade 1 radiotracer uptake and variability in follow-up intervals. Furthermore, the initiation of treatment in some individuals may have slowed or halted disease progression. All these limitations, related to the retrospective nature of this study, could potentially have led to an underestimation of the number of carriers with (probable) ATTR-CM. This study is of particular importance in the context of the upcoming ACT-EARLY trial (NCT06563895), which evaluates prophylactic therapy for ATTR amyloidosis in asymptomatic TTRv carriers. Cases with Perugini grade 1 uptake are likely to be encountered during this trial, and endomyocardial biopsies will be performed in these cases to confirm diagnosis. This study may provide definitive proof of the diagnostic value of Perugini grade 1 radiotracer uptake in TTRv carriers. Our findings, along with previous studies, suggest that Perugini grade 1 cardiac radiotracer uptake is an early marker of ATTR-CM in TTRv carriers, potentially enabling earlier diagnosis and intervention. Until further validation is available, Perugini grade 1 uptake should be considered strongly indicative of early-stage ATTR-CM in this population, provided known causes of false positives are excluded. Abbreviations ATTR-CM Transthyretin amyloid cardiomyopathy ATTRv Hereditary transthyretin amyloidosis CMR Cardiac magnetic resonance imaging ESC European Society of Cardiology GrACE Groningen Amyloidosis Centre of Expertise NT-proBNP N-terminal pro b-type natriuretic peptide SPECT/CT Single photon emission computed tomography/computed tomography TTRv Transthyretin gene variant Declarations Acknowledgements We thank Dr. P. Garcia-Pavia for his valuable comments and suggestions regarding this letter. Funding This article concerns a non-funded study. Competing interests HSA Tingen was reimbursed for traveling costs by Pfizer and Alnylam M Berends was reimbursed for traveling costs by Pfizer and Alnylam A Tubben has nothing to declare P van der Meer is supported by grant from the European Research Council (ERC CoG 101045236, DISSECT-HF) and received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis, all paid to the institute. RHJA Slart is supported by unrestricted research grants of Siemens Healthineers and Pfizer, all paid to the institute. J Bijzet has nothing to declare C Kimmich was reimbursed for traveling costs by Gilead and Janssen and received consultancy fees from Amgen, AstraZeneca, EUSA Pharma, Gilead, GSK, Incyte, Janssen, Pfizer and Sanofi-Aventis. C Knackstedt has received speaker honoraria from Pfizer and consulting fees from Bayer, Pfizer, Novartis, BMS, and Alnylam, all paid to the institute. PA van der Zwaag received consultancy fees from Pfizer, Alnylam and Novartis, all paid to the institute. FLH Muntinghe has nothing to declare EJ Houwerzijl has nothing to declare BPC Hazenberg was reimbursed for traveling costs by Pfizer HLA Nienhuis received consultancy fees from Pfizer, Alnylam and Novartis, all paid to the institute. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by H.S.A. Tingen, J. Bijzet and H.L.A. Nienhuis. The first draft of the manuscript was written by H.S.A. Tingen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the institutional review board of the University Medical Centre Groningen (registration number: 17471). Informed consent Informed consent was obtained from all individual participants included in the study. References Adams D, Koike H, Slama M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387–404. Elliott P, Drachman BM, Gottlieb SS, et al. Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy. Circ: Heart Failure. 2022;15(1):e008193. Glaudemans AWJM, van Rheenen RWJ, van den Berg MP, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid. 2014;21(1):35–44. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133(24):2404–2412. Minutoli F, Di Bella G, Mazzeo A, et al. Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation. J Nucl Cardiol. 2021;28(5):1949–1957. Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. European Heart Journal. 2021;42(16):1554–1568. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive Etiologic Diagnosis of Cardiac Amyloidosis Using 99m Tc-3,3-Diphosphono-1,2-Propanodicarboxylic Acid Scintigraphy. Journal of the American College of Cardiology. 2005;46(6):1076–1084. Rapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. European Heart Journal. 2013;34(7):520–528. Klaassen SHC, Tromp J, Nienhuis HLA, et al. Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide. The American Journal of Cardiology. 2018;121(1):107–112. Rauf MU, Hawkins PN, Cappelli F, et al. Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis. Eur Heart J. 2023;44(24):2187–2198. Cite Share Download PDF Status: Published Journal Publication published 23 May, 2025 Read the published version in European Journal of Nuclear Medicine and Molecular Imaging → Version 1 posted Editorial decision: Minor Revision 09 Apr, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Editor assigned by journal 24 Mar, 2025 First submitted to journal 24 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6275795","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":433608785,"identity":"27310b23-6af7-49cb-8fe0-00a986f62d0c","order_by":0,"name":"Hendrea Sanne Aletta Tingen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACAyjNAyY/QDiMB4jQYgDWwjgDKkqUFjDJzEOMFnMG9gcMPxj+yJjzLz722LZtm7y8A+8BvFosG3gMGHuADrOc8SzdOLfttuHGA3wJ+B12gAfkdwMegxtnzKSBWhIMgYYQ0ML+gPEPWMv5b9KWxGlhMGAG23K+h02aEahFnoGQlsM8BodlDIyBtrCZSfacu224gZmQluPtDx++qZCzNzh/+JnEj7Lb8vLtPYYP8GlhYAbFAihaJBJg9uJVjwz4oa6RbyBayygYBaNgFIwQAADPG0XRxahW+AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8572-9428","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":true,"prefix":"","firstName":"Hendrea","middleName":"Sanne Aletta","lastName":"Tingen","suffix":""},{"id":433608786,"identity":"31aa4a10-88c8-4de1-a25d-4c965116ca3d","order_by":1,"name":"M Berends","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"M","middleName":"","lastName":"Berends","suffix":""},{"id":433608787,"identity":"771983b8-10ed-40dd-ab9a-e41553deaf84","order_by":2,"name":"A Tubben","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"A","middleName":"","lastName":"Tubben","suffix":""},{"id":433608788,"identity":"fe69ebae-b1c7-4ab6-8d37-5c35dfb5fbdf","order_by":3,"name":"P van der Meer","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"P","middleName":"van der","lastName":"Meer","suffix":""},{"id":433608789,"identity":"36a0802d-d1e5-43f8-bae8-639e77ba30fc","order_by":4,"name":"R. 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Muntinghe","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"F.","middleName":"L.H.","lastName":"Muntinghe","suffix":""},{"id":433608795,"identity":"f85bc6f9-8479-464e-9006-12f85710f527","order_by":10,"name":"E. J. Houwerzijl","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"E.","middleName":"J.","lastName":"Houwerzijl","suffix":""},{"id":433608796,"identity":"72a96a03-2299-49a0-bf7c-6adbe03471c0","order_by":11,"name":"B. P.C. Hazenberg","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"B.","middleName":"P.C.","lastName":"Hazenberg","suffix":""},{"id":433608797,"identity":"7270d0f9-59db-4a93-bc35-d3af72b9e5b8","order_by":12,"name":"H. L.A. Nienhuis","email":"","orcid":"","institution":"University Medical Centre Groningen: Universitair Medisch Centrum Groningen","correspondingAuthor":false,"prefix":"","firstName":"H.","middleName":"L.A.","lastName":"Nienhuis","suffix":""}],"badges":[],"createdAt":"2025-03-21 08:52:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6275795/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6275795/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00259-025-07328-6","type":"published","date":"2025-05-23T15:57:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79809638,"identity":"88f6bc22-edcb-4ff9-9862-b09eaa87448b","added_by":"auto","created_at":"2025-04-03 06:20:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":145255,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of inclusion.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eTTRv = transthyretin gene variant; GrACE = Groningen Amyloidosis Centre of Expertise\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6275795/v1/ddab48f34ae441f5d7872c3c.png"},{"id":79810664,"identity":"320e0580-22e3-4509-8ae7-c22cf50002b0","added_by":"auto","created_at":"2025-04-03 06:36:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":123152,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSankey plot showing the study category at baseline and follow-up for each patient.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eATTR-CM = transthyretin amyloid cardiomyopathy\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6275795/v1/1ea30d2c95791e3af72eba55.png"},{"id":83460626,"identity":"4cd8abf1-e85f-4668-b71f-b8d58d3fd5fa","added_by":"auto","created_at":"2025-05-26 16:12:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1040072,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6275795/v1/f7007e90-cbb9-4d7c-a9e1-abb2d6108dae.pdf"}],"financialInterests":"","formattedTitle":"Detecting early cardiomyopathy in transthyretin variant carriers: reappraising the diagnostic value of Perugini Grade 1 radiotracer uptake on bone scintigraphy","fulltext":[{"header":"Full Text","content":"\u003cp\u003eIndividuals with a pathogenic transthyretin gene variant (\u003cem\u003eTTRv\u003c/em\u003e) are at risk for developing hereditary transthyretin (ATTRv) amyloidosis [1]. In this population, screening for ATTR cardiomyopathy (ATTR-CM), a common disease manifestation, is essential for the early detection of subclinical ATTR-CM and timely treatment initiation, which improves patient outcomes [2,3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBone scintigraphy has high accuracy for detecting ATTR-CM [4,5]. Its high accuracy and non-invasive nature make bone scintigraphy an attractive screening tool for ATTR-CM. Perugini grade 2 or 3 cardiac radiotracer uptake is diagnostic for ATTR-CM, provided there is no evidence for immunoglobulin light chain amyloidosis. In contrast, grade 1 uptake requires histological confirmation and additional findings on cardiac imaging to diagnose ATTR-CM [6]. However, in high-risk individuals such as \u003cem\u003eTTRv\u0026nbsp;\u003c/em\u003ecarriers, it may represent an early indicator of ATTR-CM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe investigated whether \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 cardiac radiotracer uptake on [\u003csup\u003e99m\u003c/sup\u003eTc]Tc-\u0026nbsp;hydroxydiphosphonate bone scintigraphy have or develop ATTR-CM. The study aimed to determine if Perugini grade 1 could be considered diagnostic of early-stage ATTR-CM in \u003cem\u003eTTRv\u003c/em\u003e carriers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study included all \u003cem\u003eTTRv\u003c/em\u003e carriers undergoing treatment or screening at the Groningen Amyloidosis Centre of Expertise (GrACE) between April 2012 and June 2023 and was approved by the ethical board of the University Medical Centre Groningen (registration number: 17471). As a part of the GrACE screening program for ATTR-CM, all \u003cem\u003eTTRv\u003c/em\u003e carriers regularly underwent bone scintigraphy, performed 3 hours after administration of 450 to 750 MBq [\u003csup\u003e99m\u003c/sup\u003eTc]Tc-hydroxydiphosphonate. Bone scintigraphy was performed on dedicated single photon emission computed tomography (SPECT)/CT systems (Symbia T2, Symbia T16 or Symbia Intevo, Siemens Healthineers, Erlangen, Germany) equipped with a low-energy high-resolution collimator. Anterior planar whole-body scans were scored according to the Perugini grading system and SPECT/CT scans were reviewed to confirm myocardial uptake [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor patients with Perugini grade 1 uptake on bone scintigraphy, data were collected from patient records until June 2024, including symptoms, cardiac biomarkers, abdominal fat tissue aspirates and tissue biopsies for amyloid detection, electrocardiography, echocardiography, cardiac magnetic resonance imaging (CMR), and bone scintigraphy. The first bone scintigraphy showing Perugini grade 1 uptake was considered the baseline scan. A descriptive analysis was performed to evaluate whether individuals met the diagnostic criteria for ATTR-CM, as outlined in the European Society of Cardiology (ESC) position paper, at baseline and follow-up [6]. \u003cem\u003eTTRv\u003c/em\u003e carriers who did not meet the ESC diagnostic criteria were classified as having \u0026lsquo;probable ATTR-CM\u0026rsquo; if they met the criteria previously used by Rapezzi et al. [8,9]. These criteria include increased wall thickness on echocardiography (end-diastolic interventricular septal and/or left ventricular posterior wall thickness \u0026ge;12 mm) and/or advanced atrioventricular block (greater than first-degree) or intraventricular conduction disturbances (bundle branch blocks/hemiblocks) on electrocardiography without an alternative explanation, combined with histologically confirmed amyloid in an extracardiac biopsy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 178 \u003cem\u003eTTRv\u003c/em\u003e carriers were screened between 2012 and 2023. Among them, 117 carriers had Perugini grade 0 (66%), 9 had grade 1 (5%), 21 had grade 2 (12%), and 31 had grade 3 (17%) cardiac radiotracer uptake on the first bone scintigraphy during screening. Notably, 3 of the 117 \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 0 uptake on their initial bone scintigraphy showed Perugini grade 1 uptake on a follow-up scan (figure 1). Clinical data were collected for the 12 \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 uptake on bone scintigraphy at any time during screening. Their \u003cem\u003eTTR\u003c/em\u003e gene variants were p.(Val50Met) (n=7), p.(Glu109Lys) (n=2), and p.(Ser43Asn) (n=1), p.(Ile127Val) (n=1), and p.(Val114Ala) (n=1). Table 1 and figure 2 provide information on whether these \u003cem\u003eTTR\u003c/em\u003ev carriers met the criteria for (probable) ATTR-CM at the baseline scan or during follow-up, along with relevant clinical parameters and details.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Fulfilment of criteria for (probable) ATTR-CM and clinical parameters in \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 cardiac radiotracer uptake\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"954\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTTRv\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst proof of amyloid in tissue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime point\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eATTR-CM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eESC echo and CMR criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerugini grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVSt on echo (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVPWt on echo (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConduction disturbances as defined in main text\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNTproBNP (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHs-cTnT (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eDiagnosis at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Ile127Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e26\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eDiagnosis at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val114Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDiagnosis during FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Ser43Asn)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2017\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt, Si\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDiagnosis during FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNo amyloid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDiagnosis during FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eProbable ATTR-CM at baseline, diagnosis during FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Glu109Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eGI biopsy, fat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt, Si\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eProbable ATTR-CM at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2021\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eOLTx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eOLTx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eProbable ATTR-CM at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eProbable ATTR-CM during FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eDuring follow-up\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e522\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eNo diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eNo amyloid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e11\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNo diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Glu109Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eDuring follow-up\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2015\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026lt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNo diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Val50Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eNerve biopsy, fat aspirate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eFU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInsufficient evidence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSt, Si\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"15\" valign=\"top\" style=\"width: 954px;\"\u003e\n \u003cp\u003eFollow-up data are presented up to the time of diagnosis, although follow-up may have continued thereafter. For \u003cem\u003eTTRv\u003c/em\u003e carriers with only a single bone scintigraphy, follow-up data from other tests are not included but may be available for assessment of cardiac status.\u003c/p\u003e\n \u003cp\u003eFU = follow-up; Pt = patient;\u003cem\u003e\u0026nbsp;TTRv\u003c/em\u003e = transthyretin gene variant; B = baseline; ESC = European Society of Cardiology; CMR = cardiac magnetic resonance imaging; IVSt = inter ventricular septal thickness; NTproBNP = N-terminal pro b-type natriuretic peptide; hs-cTnT = high sensitivity cardiac troponin T; St = transthyretin stabilizer; Si = transthyretin gene silencer; OLTx = orthotopic liver transplantation; ATTR-CM = transthyretin amyloid cardiomyopathy; GI = gastro-intestinal; \u0026dagger; = these carriers had a previous bone scintigraphy showing Perugini grade 0; \u0026Dagger; = this carrier used hydroxychloroquine.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAt baseline, 2 out of 12 \u003cem\u003eTTRv\u0026nbsp;\u003c/em\u003ecarriers met the ESC diagnostic criteria for ATTR-CM based on extracardiac biopsy and echocardiography. Three others were classified as having probable ATTR-CM at baseline. One of these carriers met the ESC diagnostic criteria after a follow-up of 3.5 years and the other 2 carriers showed worsening of cardiac parameters over follow-up periods of 4 and 12 years. Of the 7 carriers without (probable) ATTR-CM at baseline, 3 carriers were diagnosed with ATTR-CM, after a follow-up of 2, 2 and 4 years, based on Perugini grade 2 cardiac radiotracer uptake on bone scintigraphy. Of the remaining 4 carriers, 1 carrier developed probable ATTR-CM after a follow-up of 11 years, based on increased wall thickness on echocardiography and a positive fat tissue aspirate. Three carriers showed signs of cardiomyopathy during follow-up, but did not meet the criteria for ATTR-CM or probable ATTR-CM. These signs included abnormal gadolinium kinetics on CMR, reduced global longitudinal strain and increased interventricular septal thickness on echocardiography. In 1 of these carriers, bone scintigraphy results might have been false-positive due to the use of hydroxychloroquine [6]. Moreover, it is important to note that treatment for ATTRv neuropathy was initiated during follow-up for all 3 of these carriers, potentially slowing or even halting the progression of ATTR-CM.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the largest study to date that longitudinally evaluates whether \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 uptake on bone scintigraphy have or develop ATTR-CM. In 9 out of 12 \u003cem\u003eTTRv\u003c/em\u003e carriers (75%), Perugini grade 1 cardiac radiotracer uptake was indicative of (probable) ATTR-CM or its development. In 2 out of 12 individuals (17%), signs of cardiac deterioration were observed during follow-up, but were insufficient to diagnose (probable) ATTR-CM. In the remaining patient, grade 1 uptake might have been false-positive due to hydroxychloroquine use [6].\u003c/p\u003e\n\u003cp\u003eOur data highlight that cardiac radiotracer uptake on bone scintigraphy is a dynamic phenomenon. In our cohort, 3 \u003cem\u003eTTRv\u003c/em\u003e carriers initially showed no cardiac radiotracer uptake but later developed Perugini grade 1 uptake. Similarly, 4 carriers progressed from grade 1 to grade 2 uptake during follow-up. In line with our findings, Minutoli et al. previously reported a case series including 3 asymptomatic \u003cem\u003eTTRv\u003c/em\u003e carriers who developed symptoms of ATTR-CM along with cardiac abnormalities, in whom Perugini grade 1 uptake preceded these changes [5]. Consistently, Rauf et al. showed that Perugini grade 1 uptake in ATTR-CM was associated with earlier disease stages compared to higher grades according to NT-proBNP levels, echocardiography and CMR [10]. In the context of these studies, our findings provide additional support that Perugini grade 1 uptake represents early-stage ATTR-CM in \u003cem\u003eTTRv\u003c/em\u003e carriers.\u003c/p\u003e\n\u003cp\u003eMoreover, previous studies have shown that Perugini grade 1 is not an infrequent finding in ATTR-CM as it is observed in 8% of patients with endomyocardial biopsy-confirmed ATTR-CM [4]. In addition, the specificity of a positive bone scintigraphy for cardiac amyloidosis is high, ranging from 97-99% depending on the non-(cardiac) amyloidosis controls chosen [4]. Rauf et al. reported that of 3354 patients referred for suspected or proven cardiac amyloidosis, 183 had Perugini grade 1 uptake on bone scintigraphy, with 182 diagnosed with cardiac amyloidosis and only 1 false positive [10]. Further supporting the notion that \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 uptake on bone scintigraphy should be considered as having early-stage ATTR-CM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMajor limitations of our study are the absence of endomyocardial biopsies and incomplete echocardiographic and CMR data for some patients. Other limitations are the low number of patients with Perugini grade 1 radiotracer uptake and variability in follow-up intervals. Furthermore, the initiation of treatment in some individuals may have slowed or halted disease progression. All these limitations, related to the retrospective nature of this study, could potentially have led to an underestimation of the number of carriers with (probable) ATTR-CM.\u003c/p\u003e\n\u003cp\u003eThis study is of particular importance in the context of the upcoming ACT-EARLY trial (NCT06563895), which evaluates prophylactic therapy for ATTR amyloidosis in asymptomatic \u003cem\u003eTTRv\u003c/em\u003e carriers. Cases with Perugini grade 1 uptake are likely to be encountered during this trial, and endomyocardial biopsies will be performed in these cases to confirm diagnosis. This study may provide definitive proof of the diagnostic value of Perugini grade 1 radiotracer uptake in \u003cem\u003eTTRv\u003c/em\u003e carriers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur findings, along with previous studies, suggest that Perugini grade 1 cardiac radiotracer uptake is an early marker of ATTR-CM in \u003cem\u003eTTRv\u0026nbsp;\u003c/em\u003ecarriers, potentially enabling earlier diagnosis and intervention. Until further validation is available, Perugini grade 1 uptake should be considered strongly indicative of early-stage ATTR-CM in this population, provided known causes of false positives are excluded.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eATTR-CM Transthyretin amyloid cardiomyopathy\u003c/p\u003e\n\u003cp\u003eATTRv Hereditary transthyretin amyloidosis\u003c/p\u003e\n\u003cp\u003eCMR Cardiac magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003eESC European Society of Cardiology\u003c/p\u003e\n\u003cp\u003eGrACE Groningen Amyloidosis Centre of Expertise\u003c/p\u003e\n\u003cp\u003eNT-proBNP N-terminal pro b-type natriuretic peptide\u003c/p\u003e\n\u003cp\u003eSPECT/CT Single photon emission computed tomography/computed tomography\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTTRv\u003c/em\u003e Transthyretin gene variant\u003cstrong\u003e\u003cbr\u003e \u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. P. Garcia-Pavia for his valuable comments and suggestions regarding this letter.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis article concerns a non-funded study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHSA Tingen was reimbursed for traveling costs by Pfizer and Alnylam\u003c/p\u003e\n\u003cp\u003eM Berends was reimbursed for traveling costs by Pfizer and Alnylam\u003c/p\u003e\n\u003cp\u003eA Tubben has nothing to declare\u003c/p\u003e\n\u003cp\u003eP van der Meer is supported by grant from the European Research Council (ERC CoG 101045236, DISSECT-HF) and received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis, all paid to the institute.\u003c/p\u003e\n\u003cp\u003eRHJA Slart is supported by unrestricted research grants of Siemens Healthineers and Pfizer, all paid to the institute.\u003c/p\u003e\n\u003cp\u003eJ Bijzet has nothing to declare\u003c/p\u003e\n\u003cp\u003eC Kimmich was reimbursed for traveling costs by Gilead and Janssen and received consultancy fees from Amgen, AstraZeneca, EUSA Pharma, Gilead, GSK, Incyte, Janssen, Pfizer and Sanofi-Aventis.\u003c/p\u003e\n\u003cp\u003eC Knackstedt has received speaker honoraria from Pfizer and consulting fees from Bayer, Pfizer, Novartis, BMS, and Alnylam, all paid to the institute.\u003c/p\u003e\n\u003cp\u003ePA van der Zwaag received consultancy fees from Pfizer, Alnylam and Novartis, all paid to the institute.\u003c/p\u003e\n\u003cp\u003eFLH Muntinghe has nothing to declare\u003c/p\u003e\n\u003cp\u003eEJ Houwerzijl has nothing to declare\u003c/p\u003e\n\u003cp\u003eBPC Hazenberg was reimbursed for traveling costs by Pfizer\u003c/p\u003e\n\u003cp\u003eHLA Nienhuis received consultancy fees from Pfizer, Alnylam and Novartis, all paid to the institute.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by H.S.A. Tingen, J. Bijzet and H.L.A. Nienhuis. The first draft of the manuscript was written by H.S.A. Tingen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the institutional review board of the University Medical Centre Groningen (registration number: 17471). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInformed consent\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAdams D, Koike H, Slama M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387\u0026ndash;404.\u003c/li\u003e\n\u003cli\u003eElliott P, Drachman BM, Gottlieb SS, et al. Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy. Circ: Heart Failure. 2022;15(1):e008193.\u003c/li\u003e\n\u003cli\u003eGlaudemans AWJM, van Rheenen RWJ, van den Berg MP, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid. 2014;21(1):35\u0026ndash;44.\u003c/li\u003e\n\u003cli\u003eGillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133(24):2404\u0026ndash;2412.\u003c/li\u003e\n\u003cli\u003eMinutoli F, Di Bella G, Mazzeo A, et al. Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation. J Nucl Cardiol. 2021;28(5):1949\u0026ndash;1957.\u003c/li\u003e\n\u003cli\u003eGarcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. European Heart Journal. 2021;42(16):1554\u0026ndash;1568.\u003c/li\u003e\n\u003cli\u003ePerugini E, Guidalotti PL, Salvi F, et al. Noninvasive Etiologic Diagnosis of Cardiac Amyloidosis Using 99m Tc-3,3-Diphosphono-1,2-Propanodicarboxylic Acid Scintigraphy. Journal of the American College of Cardiology. 2005;46(6):1076\u0026ndash;1084.\u003c/li\u003e\n\u003cli\u003eRapezzi C, Quarta CC, Obici L, et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. European Heart Journal. 2013;34(7):520\u0026ndash;528.\u003c/li\u003e\n\u003cli\u003eKlaassen SHC, Tromp J, Nienhuis HLA, et al. Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide. The American Journal of Cardiology. 2018;121(1):107\u0026ndash;112.\u003c/li\u003e\n\u003cli\u003eRauf MU, Hawkins PN, Cappelli F, et al. Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis. Eur Heart J. 2023;44(24):2187\u0026ndash;2198.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejnm","sideBox":"Learn more about [European Journal of Nuclear Medicine and Molecular Imaging](https://www.springer.com/journal/259)","snPcode":"259","submissionUrl":"https://submission.nature.com/new-submission/259/3","title":"European Journal of Nuclear Medicine and Molecular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ATTRv, screening, ATTR-CM, diagnosis, early detection","lastPublishedDoi":"10.21203/rs.3.rs-6275795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6275795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTo determine whether \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 cardiac radiotracer uptake on [\u003csup\u003e99m\u003c/sup\u003eTc]Tc- hydroxydiphosphonate bone scintigraphy have or develop ATTR-CM.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study was conducted at the Groningen Amyloidosis Centre of Expertise between April 2012 and June 2023. \u003cem\u003eTTRv\u003c/em\u003e carriers with Perugini grade 1 uptake on bone scintigraphy were followed until to June 2024. Data on symptoms, biomarkers, imaging, and biopsies were collected. A descriptive analysis was performed to evaluate whether carriers met the diagnostic criteria for ATTR-CM or ‘probable ATTR-CM’ at baseline and follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOut of 178 \u003cem\u003eTTRv\u003c/em\u003e carriers in screening, 12 carriers had Perugini grade 1 cardiac radiotracer uptake on bone scintigraphy. At baseline, 2 carriers met the diagnostic criteria for ATTR-CM and 3 carriers met the criteria for probable ATTR-CM. Of the 7 carriers without (probable) ATTR-CM at baseline, 3 carriers were diagnosed with ATTR-CM during follow-up and 1 carrier developed probable ATTR-CM during follow-up. Three carriers showed signs of cardiomyopathy during follow-up, but did not meet the criteria for (probable) ATTR-CM. One of these cases may have been false-positive due to hydroxychloroquine use.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOur findings suggest that Perugini grade 1 cardiac radiotracer uptake is an early marker of ATTR-CM in \u003cem\u003eTTRv \u003c/em\u003ecarriers, potentially enabling earlier diagnosis and intervention.\u003c/p\u003e","manuscriptTitle":"Detecting early cardiomyopathy in transthyretin variant carriers: reappraising the diagnostic value of Perugini Grade 1 radiotracer uptake on bone scintigraphy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 06:20:21","doi":"10.21203/rs.3.rs-6275795/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor Revision","date":"2025-04-09T04:50:43+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-03-25T17:02:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T08:13:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-24T22:26:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Nuclear Medicine and Molecular Imaging","date":"2025-03-24T04:19:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejnm","sideBox":"Learn more about [European Journal of Nuclear Medicine and Molecular Imaging](https://www.springer.com/journal/259)","snPcode":"259","submissionUrl":"https://submission.nature.com/new-submission/259/3","title":"European Journal of Nuclear Medicine and Molecular Imaging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e569b517-b89b-4dba-830c-e8576cc1e08d","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:09:28+00:00","versionOfRecord":{"articleIdentity":"rs-6275795","link":"https://doi.org/10.1007/s00259-025-07328-6","journal":{"identity":"european-journal-of-nuclear-medicine-and-molecular-imaging","isVorOnly":false,"title":"European Journal of Nuclear Medicine and Molecular Imaging"},"publishedOn":"2025-05-23 15:57:52","publishedOnDateReadable":"May 23rd, 2025"},"versionCreatedAt":"2025-04-03 06:20:21","video":"","vorDoi":"10.1007/s00259-025-07328-6","vorDoiUrl":"https://doi.org/10.1007/s00259-025-07328-6","workflowStages":[]},"version":"v1","identity":"rs-6275795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6275795","identity":"rs-6275795","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}