Circulating transthyretin with atrial morpho-functional phenotypes and atrial fibrillation risk, and the modifying role of BMI

Background: Low circulating transthyretin (TTR) concentration has been suggested as a biomarker of transthyretin tetramer instability, a prerequisite for the development of transthyretin cardiac amyloidosis. This study aimed to evaluate the associations between circulating TTR levels with incident atrial fibrillation (AF) and other arrhythmias. Methods: This study used data from the UK Biobank. Participants with available TTR data and without prior arrhythmias were included. The primary outcome was new-onset AF. The secondary outcomes were new-onset supraventricular arrhythmias (SVA), bradyarrhythmias, cardiac block, and ventricular arrhythmias (VA). Multivariable Cox regression was applied to evaluate the associations between circulating TTR levels with arrhythmia outcomes. Results: A total of 40,723 participants (mean age 56.7 ± 8.2 years; 55% women) were included. After adjusting for potential confounders, one standard deviation (SD) decrease in TTR levels was associated with an increased risk of incident AF (HR 1.06, 95% CI 1.02–1.11). Furthermore, significant associations between low TTR with atrial structural remodeling were observed, manifesting as increased left atrial volume index (β 0.51, 95% CI 0.09–0.92) and right atrial volume index (β 0.87, 95% CI 0.39–1.40). In addition, there was a significant association between lower TTR levels with higher incident SVA risk, but not for bradyarrhythmias, cardiac block, or VA. A consistently significant interaction effect was identified between TTR levels and BMI for the risk of AF, SVA, bradyarrhythmias, and cardiac block (all P_interaction < 0.05), with lower TTR levels being significantly associated with a higher risk of AF (HR 1.15, 95% CI 1.06–1.26), SVA (HR 1.15, 95% CI 1.06–1.25), bradyarrhythmias (HR 1.17, 95% CI 1.05–1.30), and cardiac block (HR 1.15, 95% CI 1.02–1.29) among individuals with a BMI < 25 kg/m². In addition, carriers of likely pathogenic or pathogenic TTR variants (LP/P) had lower levels of plasma TTR compared with noncarriers, as well as higher arrhythmia risks, especially for non-Val142Ile carriers. Conclusions: Lower circulating TTR concentrations were associated with higher risk of incident AF. Exposure to low TTR and low BMI may be associated with a higher risk of AF, SVA, bradyarrhythmias, and cardiac block.