{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:11:33Z","timestamp":1789031493992,"version":"build-2803163510"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Transthyretin cardiac amyloidosis (ATTR-CA) may involve heterogeneity in biological mechanisms (ie, molecular subtypes). Molecular subtypes potentially lead to differences in prognosis and treatment response to tafamidis\u2014the first disease-modifying therapy for ATTR-CA. We aimed to derive molecular subtypes of ATTR-CA through comprehensive plasma proteomics profiling and to examine their associations with prognosis and estimated treatment effect of tafamidis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We applied unsupervised machine learning to comprehensive plasma proteomics profiling of 7289 proteins to identify molecular subtypes in our prospective cohort of patients with ATTR-CA enrolled at Columbia University. We compared all-cause mortality risk and estimated the treatment effect of tafamidis among the identified molecular subtypes, adjusting for age, sex, TTR genotype, and concomitant medication use. We also performed pathway analysis comparing the worst prognosis subtype with the other subtypes combined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Among 142 patients eligible for analysis, 96 patients received tafamidis treatment. We identified 3 molecular subtypes (subtype A: n=49, subtype B: n=38, and subtype C: n=55) with different survival risks during a median follow-up of 5.2 years (log-rank\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.035), without significant differences in traditional clinical stages. Mortality risk was highest in subtype A, followed by B and then C (eg, adjusted hazard ratio of subtype A versus C [95% CI], 1.95 [1.03\u20133.66];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.04). The largest treatment effect of tafamidis was observed in subtype A compared with no tafamidis use within the same subtype (adjusted hazard ratio for mortality, 0.24 [0.10\u20130.55]), indicating heterogeneous treatment effects of tafamidis (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      for interaction=0.001). Subtype A had dysregulation of Ras\/MAPK (mitogen-activated protein kinase) pathways, pathways implicated in ATTR-CA pathogenesis, and metabolic\/inflammatory pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our prospective cohort study using comprehensive plasma proteomics profiling not only uncovered molecular ATTR-CA subtypes but also identified pathogenetic mechanisms associated with differential prognosis and estimated the treatment effect of tafamidis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.012449","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:01:24Z","timestamp":1789030884000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomics Profiling Reveals Molecular Subtypes of Transthyretin Cardiac Amyloidosis"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7790-9130","authenticated-orcid":true,"given":"Itsuki","family":"Osawa","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-9330","authenticated-orcid":true,"given":"Sergio L.","family":"Teruya","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Bampatsias","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4498-2396","authenticated-orcid":true,"given":"Alfonsina","family":"Mirabal","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-5008","authenticated-orcid":true,"given":"Mathew S.","family":"Maurer","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3494-307X","authenticated-orcid":true,"given":"Yuichi J.","family":"Shimada","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000792"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab072"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2022.07.007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805689"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305434"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2300757"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2023.11.016"},{"key":"e_1_3_3_9_2","volume-title":"HELIOS-B: A study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathyNational Library of Medicine, ClinicalTrials.gov","year":"2024","unstructured":"HELIOS-B: A study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. National Library of Medicine, ClinicalTrials.gov. 2024. Accessed June 20, 2026. https:\/\/clinicaltrials.gov\/study\/NCT04153149"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.06.033"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx589"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2020.06.007"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2020.09.011"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2020.08.013"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy712"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2144"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2021-320729"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/1467-9868.00293"},{"key":"e_1_3_3_19_2","first-page":"2579","article-title":"Visualizing data using t-SNE.","volume":"9","author":"van der Maaten L","year":"2008","unstructured":"van der Maaten L, Hinton G. Visualizing data using t-SNE. J Mach Learn Res. 2008;9:2579\u20132605","journal-title":"J Mach Learn Res"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.7326\/M16-2607"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1092"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912263107"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.4137\/CMC.S15719"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.12.001"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.056"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25143"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.061732"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.03.429"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.12.027"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.060852"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2024.02.014"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-22116-0"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026332"},{"key":"e_1_3_3_35_2","first-page":"S5","article-title":"SOMAmers and SOMAscan \u2013 A protein biomarker discovery platform for rapid analysis of sample collections from bench top to the clinic.","volume":"24","author":"Hensley P","year":"2013","unstructured":"Hensley P. SOMAmers and SOMAscan \u2013 A protein biomarker discovery platform for rapid analysis of sample collections from bench top to the clinic. J Biomol Tech. 2013;24:S5","journal-title":"J Biomol Tech"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-019-09896-z"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.120.007849"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2023-322644"}],"container-title":["Circulation: Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCHEARTFAILURE.125.012449","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:01:31Z","timestamp":1789030891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCHEARTFAILURE.125.012449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":37,"alternative-id":["10.1161\/CIRCHEARTFAILURE.125.012449"],"URL":"https:\/\/doi.org\/10.1161\/circheartfailure.125.012449","relation":{},"ISSN":["1941-3289","1941-3297"],"issn-type":[{"value":"1941-3289","type":"print"},{"value":"1941-3297","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]},"assertion":[{"value":"2025-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e012449"}}