Transthyretin Tetramer Destabilization and Increased Mortality in the General Population.

IF 14.8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Mette Christoffersen, Anders Møller Greve, Louise Stig Hornstrup, Ruth Frikke-Schmidt, Børge Grønne Nordestgaard, Anne Tybjærg-Hansen
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引用次数: 0

Abstract

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.

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来源期刊
JAMA cardiology
JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine
CiteScore
45.80
自引率
1.70%
发文量
264
期刊介绍: JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.
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