Transthyretin Tetramer Destabilization and Increased Mortality in the General Population.

Autor:	Christoffersen M; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Greve AM; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Hornstrup LS; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark., Frikke-Schmidt R; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Nordestgaard BG; Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark.; Copenhagen City Heart Study, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark., Tybjærg-Hansen A; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Copenhagen City Heart Study, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	JAMA cardiology [JAMA Cardiol] 2024 Dec 04. Date of Electronic Publication: 2024 Dec 04.
DOI:	10.1001/jamacardio.2024.4102
Abstrakt:	Importance: Transthyretin tetramer destabilization is the rate-limiting step in the development of transthyretin cardiac amyloidosis, an underrecognized contributor to mortality in older adults. Objective: To test the hypothesis that transthyretin tetramer destabilization is associated with all-cause and cardiovascular mortality in the general population. Design, Setting, and Participants: 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. Exposures: Missense variants in TTR associated with increasing transthyretin tetramer destabilization in primary genetic analyses, and plasma transthyretin level in secondary observational analyses. Main Outcomes and Measures: All-cause and cardiovascular mortality identified from the national Danish Civil Registration System and the national Danish Register of Causes of Death. Results: A total of 102 204 individuals (median [IQR] age, 57 [47-66] years; 56 445 [55%] female) were included. Median follow-up was 10 years (range, <1-27 years). In genetic analyses, p.T139M, a transthyretin tetramer stabilizing variant that is more stable than noncarriers' 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 (P for trend = .01), and 1.63 (95% CI, 0.92-2.89) and 2.23 (95% CI, 0.78-6.34) for cardiovascular mortality (P for trend = .06). Furthermore, compared with p.T139M, plasma transthyretin decreased stepwise by TTR genotype: -18% for noncarriers and -29% for heterozygotes for amyloidogenic variants (p.V142I, p.H110N, p.D119N; P for trend < .001). Therefore, genetically determined, increasingly lower plasma transthyretin could be considered a surrogate marker for transthyretin tetramer destabilization. Observationally, among 19 619 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. Conclusions and Relevance: 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.
Databáze:	MEDLINE
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