Unraveling sex differences in transthyretin amyloidosis: Insights from the REACT-SP registry

Unraveling sex differences in transthyretin amyloidosis: Insights from the REACT-SP registry | 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 Research Article Unraveling sex differences in transthyretin amyloidosis: Insights from the REACT-SP registry Louise Freire, Christian Vicente Espinoza Romero, Bruno Vaz Kerges Bueno, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9121878/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Purpose Sex-based differences in transthyretin amyloidosis (ATTR), encompassing hereditary (ATTRv) and wildtype (ATTRwt) forms, remain underexplored due to male predominance in registries. The REACT-SP cohort, with a higher proportion of women (37.1%), provides an opportunity to assess sex-specific differences in a genetically diverse population. To evaluate sex-specific differences in clinical presentation, genotype distribution, biomarkers, cardiac involvement, diagnostic delay, and treatment access. Methods Cross-sectional analysis of 752 patients from the REACT-SP registry. Variables included age at diagnosis, time to diagnosis, phenotype, TTR mutations, biomarkers, septal thickness, and disease-modifying therapy. Sexbased comparisons were performed for the overall cohort and the ATTRv subgroup. Results Women (n=279) were diagnosed younger than men (58 vs. 68 years; p<0.003), with similar diagnostic delay. Cardiac (63.0% vs. 43.4%) and mixed phenotypes (29.8% vs. 16.8%) were more frequent in men, whereas neurological involvement showed no difference. Women had lower troponin positivity (29.3% vs. 58.8%) and septal thickness (11.0 vs. 16.5 mm; p<0.001). In ATTRv, women had lower cardiac involvement and septal thickness, and Val142Ile mutation was less frequent. Conclusion Sex significantly influences ATTR phenotype. These findings highlight the need for sex-aware diagnostic strategies, including reconsideration of septal thickness thresholds in women, to improve recognition and equitable care. Clinical trial registration Not applicable. This study is an observational analysis of data derived from a multicenter registry. transthyretin amyloidosis ATTRv ATTRwt sex differences cardiomyopathy phenotype Full Text Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 20 Mar, 2026 Reviewers invited by journal 20 Mar, 2026 Editor invited by journal 16 Mar, 2026 Editor assigned by journal 16 Mar, 2026 First submitted to journal 14 Mar, 2026 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. 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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-9121878","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":609478312,"identity":"a441bab0-9486-4a9b-9dbd-f3f81a91266a","order_by":0,"name":"Louise Freire","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIie3Pv2uDQBTA8SeBc8mP9UJA/4LCBaF0KPpfdH4S0CWBTKVTcbq/IcGh/0Kk0KnDC0ImyT+Qobp0vmzZWjWrmmYL9L6DwvE+vDsAne4WIzAIgAP0yh8CWPVh3k3gTBjWxKkP8TKBMynzo+rbRYaHNKejfPBGbFDkxedj+PaUFuUW17qLmsl4H4jtWnJ/LU1H4HewSA6BKMnMuadmIjIQ6UByFF+ScaR0kcRYEfI/WompKuJ5O2aekH7CaRyqC6RfbzE2jDFAIrQn8+4t46y/3K723F/tWK+82Gy6mcyXhKL9LcPMTHL1/OqNJDOOJ3JtOw7flXpxrTbScNV6Uvx1vMqOrpnW6XS6/9AvyMBls0Xb/S4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0002-1281-4338","institution":"FMUSP: Universidade de Sao Paulo Faculdade de Medicina","correspondingAuthor":true,"prefix":"","firstName":"Louise","middleName":"","lastName":"Freire","suffix":""},{"id":609478313,"identity":"e84675c0-b079-4ac6-a2d1-1a48677fd8f2","order_by":1,"name":"Christian Vicente Espinoza Romero","email":"","orcid":"","institution":"FMUSP: Universidade de Sao Paulo Faculdade de Medicina","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"Vicente Espinoza","lastName":"Romero","suffix":""},{"id":609478314,"identity":"aacf4359-44a2-444b-af8e-cea9a8f6dc42","order_by":2,"name":"Bruno Vaz Kerges Bueno","email":"","orcid":"","institution":"FMUSP: Universidade de Sao Paulo Faculdade de Medicina","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"Vaz Kerges","lastName":"Bueno","suffix":""},{"id":609478315,"identity":"5408e81b-9dc1-48dd-8e73-67af3254e92d","order_by":3,"name":"Andre Luiz Dabarian","email":"","orcid":"","institution":"FMUSP: Universidade de Sao Paulo Faculdade de Medicina","correspondingAuthor":false,"prefix":"","firstName":"Andre","middleName":"Luiz","lastName":"Dabarian","suffix":""},{"id":609478316,"identity":"da9face7-0241-4aae-bb20-b66a5365ad5d","order_by":4,"name":"Edileide Barros Correia","email":"","orcid":"","institution":"Instituto Dante Pazzanese de Cardiologia","correspondingAuthor":false,"prefix":"","firstName":"Edileide","middleName":"Barros","lastName":"Correia","suffix":""},{"id":609478317,"identity":"d8ca4be0-c829-4ed2-ab9b-ff2e581678ec","order_by":5,"name":"Alzira Alves Siqueira Carvalho","email":"","orcid":"","institution":"Faculdade de Medicina do ABC","correspondingAuthor":false,"prefix":"","firstName":"Alzira","middleName":"Alves Siqueira","lastName":"Carvalho","suffix":""},{"id":609478318,"identity":"7a4a6b94-d2f1-4683-9baa-b7d02e660195","order_by":6,"name":"Ariane Vieira Scarlatelli Macedo","email":"","orcid":"","institution":"Irmandade da Santa Casa de Misericordia de Sao Paulo","correspondingAuthor":false,"prefix":"","firstName":"Ariane","middleName":"Vieira Scarlatelli","lastName":"Macedo","suffix":""},{"id":609478319,"identity":"f2b66eb2-fc3e-4556-93af-146cebfdc535","order_by":7,"name":"Otavio Rizzi Coelho-Filho","email":"","orcid":"","institution":"UNICAMP: Universidade Estadual de Campinas","correspondingAuthor":false,"prefix":"","firstName":"Otavio","middleName":"Rizzi","lastName":"Coelho-Filho","suffix":""},{"id":609478320,"identity":"45dd629f-fb95-4e25-a906-d6c82df2c09b","order_by":8,"name":"Phillip Scheinberg","email":"","orcid":"","institution":"Beneficência Portuguesa de São Paulo: Beneficencia Portuguesa de Sao Paulo","correspondingAuthor":false,"prefix":"","firstName":"Phillip","middleName":"","lastName":"Scheinberg","suffix":""},{"id":609478321,"identity":"37108ac1-af27-415a-968d-4dbf97919f72","order_by":9,"name":"Murillo Oliveira Antunes","email":"","orcid":"","institution":"Universidade Sao Francisco - 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The REACT-SP cohort, with a higher proportion of women (37.1%), provides an opportunity to assess sex-specific differences in a genetically diverse population. To evaluate sex-specific differences in clinical presentation, genotype distribution, biomarkers, cardiac involvement, diagnostic delay, and treatment access.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eCross-sectional analysis of 752 patients from the REACT-SP registry. Variables included age at diagnosis, time to diagnosis, phenotype, TTR mutations, biomarkers, septal thickness, and disease-modifying therapy. Sexbased comparisons were performed for the overall cohort and the ATTRv subgroup.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eWomen (n=279) were diagnosed younger than men (58 vs. 68 years; p\u0026lt;0.003), with similar diagnostic delay. Cardiac (63.0% vs. 43.4%) and mixed phenotypes (29.8% vs. 16.8%) were more frequent in men, whereas neurological involvement showed no difference. Women had lower troponin positivity (29.3% vs. 58.8%) and septal thickness (11.0 vs. 16.5 mm; p\u0026lt;0.001). In ATTRv, women had lower cardiac involvement and septal thickness, and Val142Ile mutation was less frequent. \u003cstrong\u003eConclusion \u003c/strong\u003eSex significantly influences ATTR phenotype. These findings highlight the need for sex-aware diagnostic strategies, including reconsideration of septal thickness thresholds in women, to improve recognition and equitable care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. 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