{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:06:27Z","timestamp":1793423187059,"version":"4.5.0"},"reference-count":27,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2025,2,1]]},"abstract":"<jats:sec id=\"ab-hoi240067-4\"><jats:title>Importance<\/jats:title><jats:p>Transthyretin tetramer destabilization is the rate-limiting step in the development of transthyretin cardiac amyloidosis, an underrecognized contributor to mortality in older adults.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-5\"><jats:title>Objective<\/jats:title><jats:p>To test the hypothesis that transthyretin tetramer destabilization is associated with all-cause and cardiovascular mortality in the general population.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>In this cohort study including individuals aged 20 to 80 years, genetic data were analyzed from 2 similar prospective studies of the Danish general population, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Observational data from a subsample of the same studies where transthyretin was measured consecutively were also analyzed. In both studies, individuals were followed up from the examination date (1991-1994 in CCHS and 2003-2015 in CGPS) until death or the end of follow-up in December 2018. Data were analyzed from November 1, 2023, to August 15, 2024.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-7\"><jats:title>Exposures<\/jats:title><jats:p>Missense variants in <jats:italic>TTR<\/jats:italic> associated with increasing transthyretin tetramer destabilization in primary genetic analyses, and plasma transthyretin level in secondary observational analyses.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>All-cause and cardiovascular mortality identified from the national Danish Civil Registration System and the national Danish Register of Causes of Death.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-9\"><jats:title>Results<\/jats:title><jats:p>A total of 102\u202f204 individuals (median [IQR] age, 57 [47-66] years; 56\u202f445 [55%] female) were included. Median follow-up was 10 years (range, &amp;amp;lt;1-27 years). In genetic analyses, p.T139M, a transthyretin tetramer stabilizing variant that is more stable than noncarriers\u2019 tetramer stability, was used as the reference. For noncarriers who have intermediate tetramer stability and for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, and p.D119N) who have the lowest tetramer stability, respective hazard ratios (HRs) were 1.37 (95% CI, 1.06-1.77) and 1.65 (95% CI, 0.95-2.88) for all-cause mortality (<jats:italic>P<\/jats:italic> for trend\u2009=\u2009.01), and 1.63 (95% CI, 0.92-2.89) and 2.23 (95% CI, 0.78-6.34) for cardiovascular mortality (<jats:italic>P<\/jats:italic> for trend\u2009=\u2009.06). Furthermore, compared with p.T139M, plasma transthyretin decreased stepwise by <jats:italic>TTR<\/jats:italic> genotype: \u221218% for noncarriers and \u221229% for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, p.D119N; <jats:italic>P<\/jats:italic> for trend\u2009&amp;amp;lt;\u2009.001). Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization. Observationally, among 19\u202f619 individuals, noncarriers with plasma transthyretin concentrations less than 20 mg\/dL vs 20 to 40 mg\/dL had HRs of 1.12 (95% CI, 1.02-1.23) for all-cause mortality and 1.16 (95% CI, 0.97-1.39) for cardiovascular mortality.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240067-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Transthyretin tetramer destabilization was associated with all-cause and cardiovascular mortality in the Danish general population. These findings may suggest a need for large-scale assays to measure transthyretin destabilization for detection of transthyretin amyloidosis before clinical manifestations emerge, since early treatment improves the prognosis.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamacardio.2024.4102","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T16:00:58Z","timestamp":1733328058000},"page":"155","source":"Crossref","is-referenced-by-count":19,"title":["Transthyretin Tetramer Destabilization and Increased Mortality in the General Population"],"prefix":"10.1001","volume":"10","author":[{"given":"Mette","family":"Christoffersen","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders M\u00f8ller","family":"Greve","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise Stig","family":"Hornstrup","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Frikke-Schmidt","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"},{"name":"Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00f8rge Gr\u00f8nne","family":"Nordestgaard","sequence":"additional","affiliation":[{"name":"Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark"},{"name":"Copenhagen City Heart Study, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Tybj\u00e6rg-Hansen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"},{"name":"Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"name":"Copenhagen City Heart Study, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"13","key":"hoi240067r1","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1056\/NEJM199709253371306","article-title":"The systemic amyloidoses.","volume":"337","author":"Falk","year":"1997","journal-title":"N Engl J Med"},{"issue":"5","key":"hoi240067r2","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1042\/CS20160413","article-title":"Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy.","volume":"131","author":"Galant","year":"2017","journal-title":"Clin Sci (Lond)"},{"issue":"9","key":"hoi240067r3","doi-asserted-by":"publisher","first-page":"2817","DOI":"10.1073\/pnas.0400062101","article-title":"Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture.","volume":"101","author":"Reixach","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"47","key":"hoi240067r4","doi-asserted-by":"publisher","first-page":"15525","DOI":"10.1021\/bi051608t","article-title":"The pathway by which the tetrameric protein transthyretin dissociates.","volume":"44","author":"Foss","year":"2005","journal-title":"Biochemistry"},{"issue":"6","key":"hoi240067r5","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1161\/ATVBAHA.113.301273","article-title":"Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy.","volume":"33","author":"Hornstrup","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"hoi240067r6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/00000441-198501000-00003","article-title":"Lowered prealbumin levels in patients with familial amyloid polyneuropathy (FAP) and their non-affected but at risk relatives.","volume":"289","author":"Skinner","year":"1985","journal-title":"Am J Med Sci"},{"issue":"2","key":"hoi240067r7","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCHEARTFAILURE.117.004000","article-title":"Use of serum transthyretin as a prognostic indicator and predictor of outcome in cardiac amyloid disease associated with wild-type transthyretin.","volume":"11","author":"Hanson","year":"2018","journal-title":"Circ Heart Fail"},{"issue":"3","key":"hoi240067r8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.jacc.2019.03.012","article-title":"Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy.","volume":"74","author":"Judge","year":"2019","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"hoi240067r9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/cpdd.700","article-title":"First-in-human study of AG10, a novel, oral, specific, selective, and potent transthyretin stabilizer for the treatment of transthyretin amyloidosis: a phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy adult volunteers.","volume":"9","author":"Fox","year":"2020","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"6","key":"hoi240067r10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X","article-title":"Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort.","volume":"13","author":"Ritchie","year":"1999","journal-title":"J Clin Lab Anal"},{"issue":"3","key":"hoi240067r11","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1001\/jamacardio.2020.5969","article-title":"Association of low plasma transthyretin concentration with risk of heart failure in the general population.","volume":"6","author":"Greve","year":"2021","journal-title":"JAMA Cardiol"},{"issue":"1","key":"hoi240067r12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cell.2005.01.018","article-title":"The biological and chemical basis for tissue-selective amyloid disease.","volume":"121","author":"Sekijima","year":"2005","journal-title":"Cell"},{"issue":"6","key":"hoi240067r13","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1399-0004.1994.tb04030.x","article-title":"Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis.","volume":"45","author":"Skare","year":"1994","journal-title":"Clin Genet"},{"issue":"1-2","key":"hoi240067r14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jns.2009.04.015","article-title":"Transthyretin Asn90 variant: amyloidogenic or non-amyloidogenic role.","volume":"284","author":"Bersano","year":"2009","journal-title":"J Neurol Sci"},{"issue":"2","key":"hoi240067r15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3109\/13506129.2011.560215","article-title":"Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred.","volume":"18","author":"Groenning","year":"2011","journal-title":"Amyloid"},{"issue":"7","key":"hoi240067r16","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1056\/NEJM199702133360703","article-title":"Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.","volume":"336","author":"Jacobson","year":"1997","journal-title":"N Engl J Med"},{"issue":"3","key":"hoi240067r17","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1006\/bbrc.2000.2554","article-title":"Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M.","volume":"270","author":"Almeida","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"issue":"5539","key":"hoi240067r18","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1126\/science.1062245","article-title":"Trans-suppression of misfolding in an amyloid disease.","volume":"293","author":"Hammarstr\u00f6m","year":"2001","journal-title":"Science"},{"issue":"5607","key":"hoi240067r19","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1126\/science.1079589","article-title":"Prevention of transthyretin amyloid disease by changing protein misfolding energetics.","volume":"299","author":"Hammarstr\u00f6m","year":"2003","journal-title":"Science"},{"issue":"6","key":"hoi240067r20","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification.","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans Automat Contr"},{"issue":"11","key":"hoi240067r21","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1056\/NEJMoa1805689","article-title":"Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.","volume":"379","author":"Maurer","year":"2018","journal-title":"N Engl J Med"},{"issue":"3","key":"hoi240067r22","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1161\/CIRCULATIONAHA.115.018852","article-title":"Heart failure resulting from age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study.","volume":"133","author":"Connors","year":"2016","journal-title":"Circulation"},{"issue":"2","key":"hoi240067r23","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ahj.2012.04.015","article-title":"Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS).","volume":"164","author":"Ruberg","year":"2012","journal-title":"Am Heart J"},{"issue":"2","key":"hoi240067r24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s40259-023-00577-7","article-title":"RNA targeting and gene editing strategies for transthyretin amyloidosis.","volume":"37","author":"Ioannou","year":"2023","journal-title":"BioDrugs"},{"issue":"3","key":"hoi240067r25","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/ejhf.1742","article-title":"Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies.","volume":"22","author":"Milandri","year":"2020","journal-title":"Eur J Heart Fail"},{"issue":"1","key":"hoi240067r26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jacc.2019.04.054","article-title":"Association of carpal tunnel syndrome with amyloidosis, heart failure, and adverse cardiovascular outcomes.","volume":"74","author":"Fosb\u00f8l","year":"2019","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"hoi240067r27","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1093\/oxfordjournals.aje.a010013","article-title":"Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.","volume":"150","author":"Clarke","year":"1999","journal-title":"Am J Epidemiol"}],"container-title":["JAMA Cardiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/articlepdf\/2827200\/jamacardiology_christoffersen_2024_oi_240067_1738111889.92782.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T16:01:48Z","timestamp":1739376108000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/fullarticle\/2827200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,1]]},"references-count":27,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamacardio.2024.4102","relation":{},"ISSN":["2380-6583"],"issn-type":[{"value":"2380-6583","type":"print"}],"subject":[],"published":{"date-parts":[[2025,2,1]]}}}