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

Abstract

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. 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. 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. 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.