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Cardiology

Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population

Educational Objective
To understand the role of plasma transthyretin (ie, prealbumin) in the pathogenesis of amyloidogenic transthyretin cardiac amyloidosis.

1 Credit CME

JAMA Cardiology

Published Online: November 25, 2020

Original Investigation

Article Information and Disclosures

Anders M. Greve, MD, PhD¹;

Mette Christoffersen, MSc, PhD¹;

Ruth Frikke-Schmidt, MD, DMSc^1,2,3;

Børge G. Nordestgaard, MD, DMSc^2,3,4;

Anne Tybjærg-Hansen, MD, DMSc^1,2,3,4

Author Affiliations

¹Section for Molecular Genetics, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
²Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
³Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
⁴The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark

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Key Points

Question Is low plasma transthyretin, which can be indicative of transthyretin protein misfolding, associated with incident heart failure (HF) in the general population?

Findings In 2 cohort studies of the general population including 16 967 individuals, transthyretin levels at or below the 5th percentile were associated with incident HF compared with levels in the 5th to 95th percentile. Genetic variants in TTR were also associated with lower transthyretin concentrations and higher risk of incident HF in these 2 cohort studies.

Meaning Low plasma transthyretin may be a risk factor for HF in the general population.

Abstract

Importance Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown.

Objective To evaluate whether low plasma transthyretin concentration is associated with incident HF in the general population.

Design, Setting, and Participants This study included data from 2 similar prospective cohort studies of the Danish general population, the Copenhagen General Population Study (CGPS; n = 9582) and the Copenhagen City Heart Study (CCHS; n = 7385). Using these data, first, whether low concentration of plasma transthyretin was associated with increased risk of incident HF was tested. Second, whether genetic variants in TTR associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of HF was tested. Data were collected from November 2003 to March 2017 in the CGPS and from November 1991 to June 1994 in the CCHS; participants from both studies were observed for survival time end points until March 2017. Data were analyzed from March to June 2019.

Exposures Transthyretin concentration at or below the 5th percentile, between the 5th and 95th percentile (reference), and greater than the 95th percentile; genetic variants in TTR.

Main Outcome and Measure Incident HF identified using the Danish National Patient Registry.

Results Of 9582 individuals in the CGPS, 5077 (53.0%) were women, and the median (interquartile range [IQR]) age was 56 (47-65) years. Of 7385 individuals in the CCHS, 4452 (60.3%) were women, and the median (IQR) age was 59 (46-70) years. During a median (IQR) follow-up of 12.6 (12.3-12.9) years and 21.7 (11.6-23.8) years, 441 individuals (4.6%) in the CGPS and 1122 individuals (15.2%) in the CCHS, respectively, developed HF. Baseline plasma transthyretin concentrations at or below the 5th percentile were associated with incident HF (CGPS: hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; CCHS: HR, 1.4; 95% CI, 1.1-1.7). Risk of HF was highest in men with low transthyretin levels. Compared with p.T139M, a transthyretin-stabilizing variant, TTR genotype was associated with stepwise lower transthyretin concentrations for wild-type TTR (−16.5%), p.G26S (−18.1%), and heterozygotes for other variants (p.V142I, p.H110N, and p.D119N; −30.8%) (P for trend <.001). The corresponding HRs for incident HF were 1.14 (95% CI, 0.57-2.28), 1.29 (95% CI, 0.64-2.61), and 2.04 (95% CI, 0.54-7.67), respectively (P for trend = .04).

Conclusions and Relevance In this study, lower plasma and genetically determined transthyretin concentrations were associated with a higher risk of incident HF, suggesting a potential mechanistic association between low transthyretin concentration as a marker of tetramer instability and incident HF in the general population.

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Article Information

Accepted for Publication: September 4, 2020.

Published Online: November 25, 2020. doi:10.1001/jamacardio.2020.5969

Corresponding Author: Anne Tybjærg-Hansen, MD, DMSc, Section for Molecular Genetics, Department of Clinical Biochemistry KB 3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (anne.tybjaerg.hansen@regionh.dk).

Author Contributions: Dr Tybjærg-Hansen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Greve, Christoffersen, Tybjærg-Hansen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Greve, Christoffersen, Tybjærg-Hansen.

Critical revision of the manuscript for important intellectual content: Christoffersen, Frikke-Schmidt, Nordestgaard, Tybjærg-Hansen.

Statistical analysis: Greve, Christoffersen, Tybjærg-Hansen.

Obtained funding: Nordestgaard, Tybjærg-Hansen.

Administrative, technical, or material support: Frikke-Schmidt, Tybjærg-Hansen.

Study supervision: Frikke-Schmidt, Nordestgaard, Tybjærg-Hansen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by The Research Fund at Rigshospitalet, Copenhagen University Hospital, Chief Physician Johan Boserup and Lise Boserup’s Fund, Ingeborg and Leo Dannin’s Grant, and Henry Hansen’s and Wife’s Grant and a grant from the Odd Fellow Order.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are indebted to the staff and participants of the Copenhagen General Population Study and the Copenhagen City Heart Study for their important contributions.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.