{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:28:45Z","timestamp":1780446525463,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alnylam Pharmaceuticals\u00ae","award":["PO 4510001138"],"award-info":[{"award-number":["PO 4510001138"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In transthyretin cardiac amyloidosis (ATTR-CA), misfolded transthyretin accumulates in the myocardium, leading to wall thickening and interstitial fibrosis. Recently published in vitro studies revealed direct effects of transthyretin on the structure, function, and gene expression of cardiac fibroblasts. Therefore, we hypothesized that biomarkers known to modulate myocardial remodeling might be clinically valuable in ATTR-CA and may improve risk stratification in ATTR-CA. To analyze this hypothesis, we evaluated 14 fibrosis-related biomarkers (EN-RAGE, IGFBP-1, -2, -3, -4, -6, FGF-23, MMP-2, -7, -9, -13, TIMP-2, -4, and RAGE-AGE) in 125 patients using Luminex multiplex assays. The study cohort consists of 14 asymptomatic gene carriers (ATTRv-asymp), 47 symptomatic hereditary (ATTRv-CA), 43 wild-type Transthyretin amyloidosis (ATTRwt) patients, and 21 were healthy controls (ctrl). Associations of fibrotic biomarkers and clinical routine data with clinical outcomes\u2014cardiac decompensation (DMP) and transplantation\/death (HTX)\u2014were assessed via hierarchical cluster analysis, regression, and prediction modeling. We found that ATTR-CA patients showed distinct biomarker profiles compared to controls. Several markers (e.g., MMP-7, RAGE-AGE, IGFBP-1, FGF-23, TIMP-2) were significantly associated with both endpoints. Cluster analysis identified a high-risk phenotype (Cluster 2) with worse renal function, greater myocardial thickening, and elevated NT-proBNP, hsTNT. Prediction modeling revealed IGFPB-1, -3, -4 and -6 as well as FGF-23, TIMP-2, and RAGE\/AGE as the best predictive parameters for cluster assignment. Taken together, these findings confirm our hypothesis that fibrosis-related biomarkers are associated with adverse outcomes in ATTR-CM. Profibrotic mediators such as IGFBP-1, FGF-23, and TIMP-2 may, therefore, provide additional prognostic information beyond established cardiac biomarkers and may reflect underlying fibrotic remodeling pathways.<\/jats:p>","DOI":"10.3390\/ijms262110714","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:11:16Z","timestamp":1762254676000},"page":"10714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Profibrotic Biomarkers Correlate with Clinical Presentation and Outcome in Cardiac Transthyretin Amyloidosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-4200","authenticated-orcid":false,"given":"Selina J.","family":"Hein","sequence":"first","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4264-1722","authenticated-orcid":false,"given":"Fabian","family":"aus dem Siepen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7657-3700","authenticated-orcid":false,"given":"Arnt V.","family":"Kristen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-5579","authenticated-orcid":false,"given":"Stefan","family":"Sch\u00f6nland","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Rheumatology, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1917-6746","authenticated-orcid":false,"given":"Ute","family":"Hegenbart","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Rheumatology, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Rein","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Division of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany"},{"name":"CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2293-2314","authenticated-orcid":false,"given":"Hugo A.","family":"Katus","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-378X","authenticated-orcid":false,"given":"Norbert","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1964-4098","authenticated-orcid":false,"given":"Jennifer","family":"Furkel","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Division of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany"},{"name":"CCU Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-1039","authenticated-orcid":false,"given":"Mathias H.","family":"Konstandin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-3980","authenticated-orcid":false,"given":"Maximilian","family":"Knoll","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK) Core-Center, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Division of Molecular & Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany"},{"name":"Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), German Cancer Research Center (DKFZ) and Heidelberg 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