Serum Transthyretin as Prognostic Biomarker for Cardiovascular Events and Mortality

Abstract

Background

Serum transthyretin (TTR) levels, a key player in the occurrence of amyloidosis, have also emerged as a potential biomarker in cardiovascular (CV) disease and all-cause mortality. However, it is unclear whether TTR levels predict future events.

Objectives

This meta-analysis sought to evaluate the prognostic utility in longitudinal studies of serum TTR levels in predicting CV events, heart failure (HF), CV mortality, and all-cause mortality across diverse patient populations.

Methods

A systematic literature search was conducted across major electronic databases and gray literature up to May 2025. Studies reporting HRs or risk estimates for the association between serum TTR levels and outcomes of interest (CV events and mortality) were included. Two reviewers extracted data independently and summary estimates of association were obtained using a random-effects model. The primary outcomes were risk ratios for total CV events, HF, all-cause mortality, and CV mortality.

Results

A total of 34 studies involving 83,929 participants, 50.5% females, mean age 61.45 years old, and a mean follow-up of 41 months were included in the analysis. Low serum TTR levels were found to be significantly associated with an increased risk of CV events (HR: 1.54; 95% CI: 1.30-1.83; P < 0.001), all-cause mortality (HR: 1.65; 95% CI: 1.50-1.82; P < 0.001), CV mortality (HR: 2.08; 95% CI: 1.26-3.44; P = 0.004), and heart failure (HR: 1.72; 95% CI: 1.35-2.21; P < 0.001). A decrease in TTR by 10 mg/dL corresponded with an increase in risk of 30%, 73%, 46%, and 28% in total CV, all-cause mortality, CV mortality, and HF, respectively. In meta-regression analysis, low TTR levels in younger male subjects, preserved ejection fraction and elevated N-terminal pro-B-type natriuretic peptide levels were associated with a higher risk of all-cause mortality.

Conclusions

Serum TTR is a predictor of CV events, all-cause and CV mortality, and HF across different populations, underscoring its potential use as a CV biomarker and instigating research on the possible clinical role of TTR medications in other clinical settings other than amyloidosis.