Baseline characteristics
After excluding participants without available data of baseline TTR (n = 457,805), those with prior AF diagnosis (n = 881), and with missing values on any covariate (n = 2761), we finally included 40,723 participants (mean age 56.7 ± 8.2, 55% women) in the primary analysis (Additional file 1: Fig. S2).
Table 1 presents the baseline characteristics of the included participants stratified by TTR levels. The median [IQR] levels of TTR in females [− 0.1 (− 0.3, 0.1)] were significantly lower than males [0.1 (− 0.1, 0.3)] (Additional file 1: Fig. S1). Participants with lower circulating TTR had a higher prevalence of coronary artery disease and diabetes, as well as a lower risk of baseline hypertension.
Table 1 Baseline characteristics of the included individuals for the association between TTR with atrial fibrillationThe association between TTR levels with incident AF and atrial morpho-functional phenotypes
Over 561,705 person-years of follow-up (median follow-up 14.6 [IQR 13.7, 15.4] years), 2930 (7.2%) participants developed new-onset AF (5.22 per 1000 person-years). The cumulative incidence of AF was higher among individuals in the lower tertiles of circulating TTR (Fig. 1A). In individuals with high, intermediate, and low TTR levels, the incidence rate of AF was 4.79 (95% CI, 4.48–5.11), 5.13 (95% CI, 4.81–5.46), and 5.75 (95% CI, 5.41–6.10) per 1000 person-years, respectively.
Fig. 1
Cumulative curves of outcomes stratified by transthyretin tertiles. Cumulative curves of incident A atrial fibrillation, B supraventricular arrhythmias, C bradyarrhythmias, D cardiac block, and E ventricular arrhythmias in the study population. Log-rank tests were used. Abbreviation: TTR, transthyretin
A decrease in circulating TTR levels was associated with significantly increased risk of new-onset AF, consistent across three models (Table 2). In the fully adjusted model, the risk of AF increased by 6% per SD decrease in TTR levels [HR, 1.06; 95% CI (1.02, 1.11); p = 0.005], which was further supported by the RCS curve between TTR and AF (Fig. 2A). After adjusting for covariates, the RCS analyses demonstrated a steeper negative slope among individuals with lower TTR levels (P non-linear = 0.001), suggesting that lower circulating TTR concentrations were associated with higher risk of incident AF.
Table 2 The associations between circulating TTR with incident arrhythmiasFig. 2
Risk of incident cardiac arrhythmias by circulating transthyretin levels in the study population. Risk of incident A atrial fibrillation, B supraventricular arrhythmias, C bradyarrhythmias, D cardiac block, and E ventricular arrhythmias by circulating transthyretin levels in the study population. Orange lines and shaded areas depict restricted cubic spline curves based on model 3. The blue density function displays distribution of baseline circulating transthyretin concentration. Restricted cubic spline analyses were based on the fully adjusted model, accounting for age, sex, race, body mass index, smoking status, drinking status, total cholesterol, estimated glomerular filtration rate, triglyceride, low-density lipoprotein cholesterol, heart failure, diabetes, hypertension, coronary artery disease, valvular disease, chronic kidney disease, obstructive sleep apnea, antihypertensive medication, and cholesterol-lowering medication. Abbreviation: TTR, transthyretin
Among the individuals with TTR data, CMR data were available for 3402. The baseline characteristics between those with and without CMR data are presented in Additional file 1: Table S3. Individuals with available CMR data were younger, more likely to be male, and had a lower prevalence of comorbidities. After fully adjusting for potential confounders, per SD decrease in circulating TTR levels was associated with significantly larger volume indices for both the left and right atria, including left atrial maximum volume [LAVmax, β = 0.96; 95% CI (0.12, 1.80); p = 0.025], LAVmax indexed to body surface area [LAVimax, β = 0.51; 95% CI (0.09, 0.92); p = 0.017], right atrial maximum volume [RAVmax, β = 1.50; 95% CI (0.56, 2.40); p = 0.002], RA minimum volume [RAVmin, β = 0.78; 95% CI (0.15, 1.40); p = 0.015], RAVmax index [RAVimax, β = 0.87; 95% CI (0.39, 1.40); p β = 0.45; 95% CI (0.12, 0.77); p = 0.007] (Additional file 1: Table S4).
For atrial functional parameters, per SD decrease in circulating TTR levels was associated with increased LA total emptying volume [LATEV, β = 0.44; 95% CI (0.02, 0.85); p = 0.038] and RA total emptying volume [RATEV, β = 0.69; 95% CI (0.23, 1.20); p = 0.003], but not for LA total emptying fraction [LATEF, β = − 0.06; 95% CI (− 0.40, 0.27); p = 0.700] or RA total emptying fraction [RATEF, β = 0.06; 95% CI (− 0.27, 0.39); p = 0.700] (Additional file 1: Table S4). Analyses investigating the interaction between TTR levels and the time interval (between baseline and imaging visit date) did not find any significant results (Additional file 1: Table S4).
Sensitivity analyses and subgroup analyses
Results from all the sensitivity analyses were consistent with the primary analyses (Additional file 1: Tables S5 and S6). Lower plasma TTR levels were associated with significantly increased AF risk after excluding AF cases within the first year of follow-up [HR, 1.06; 95% CI (1.02, 1.11); p = 0.007], those with baseline heart failure, coronary artery disease and VHD [HR, 1.06; 95% CI (1.02, 1.11); p = 0.009], and individuals with baseline thyroid dysfunction [HR, 1.06; 95% CI (1.02, 1.11); p = 0.006] or using sub-distribution hazard model [HR, 1.06; 95% CI (1.02, 1.10); p = 0.006]. Besides, the association remained significant after further adjustment for dietary retinol intake [HR, 1.06; 95% CI (1.02, 1.11); p = 0.005] (Additional file 1: Table S5). When treating TTR as a categorical variable, compared to individuals with high TTR levels, those in the lowest tertile presented with significantly higher AF risk [HR, 1.11; 95% CI (1.01, 1.22); p = 0.025] (Additional file 1: Table S6).
Subgroup analyses observed that compared to individuals with a higher BMI, the association between TTR and AF risk was greater among those with a BMI 2 (Fig. 3). Significant interaction of BMI on the associations between TTR and AF was observed (Pinteraction = 0.003; FDR-corrected Pinteraction = 0.013) (Fig. 4A). Besides, the associations between lower TTR and increased AF risk were greater among individuals with an older age (Pinteraction Pinteraction
Fig. 3
Subgroup analyses for the association between circulating transthyretin levels with incident AF. Multivariable cox analyses were based on the fully adjusted model, accounting for age, sex, race, body mass index, smoking status, drinking status, total cholesterol, estimated glomerular filtration rate, triglyceride, low-density lipoprotein cholesterol, heart failure, diabetes, hypertension, coronary artery disease, valvular disease, chronic kidney disease, obstructive sleep apnea, antihypertensive medication, and cholesterol-lowering medication. Abbreviations: AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; TTR, transthyretin
Fig. 4
The interaction effects of BMI and transthyretin levels for the risk of cardiac arrhythmias. The interaction effects of BMI and transthyretin levels for the risk of incident A atrial fibrillation, B supraventricular arrhythmias, C bradyarrhythmias, D cardiac block, and E ventricular arrhythmias. Abbreviations: BMI, body mass index; TTR, transthyretin
Additionally, there was a significant association between TTR and AF among individuals with low PRS, but not for those in intermediate or high PRS group (Pinteraction Pinteraction 3).
The association between TTR levels with secondary outcomes
During follow-up, new-onset SVA, bradyarrhythmias, cardiac block, and VA developed in 3098 (7.6%), 2016 (4.9%), 1590 (3.8%), and 701 (1.7%) participants, respectively. As shown in the Kaplan–Meier curves (Fig. 1B, C, D, E), the cumulative incidence of each outcome was higher among individuals in the lower tertiles of circulating TTR (all log-rank p
Lower plasma TTR levels were associated with significantly higher risk for SVA [per SD decrease TTR: HR, 1.07; 95% CI (1.03, 1.12); p 2). Similar to AF, the multivariable RCS analyses for SVA (Fig. 2B), bradyarrhythmias (Fig. 2C), and cardiac block (Fig. 2D) all demonstrated a steeper negative slope among individuals with lower TTR levels (all P non-linear 2E).
Similar to AF, subgroup analyses suggested an association between lower TTR levels with higher SVA [HR, 1.15; 95% CI (1.06, 1.25); p HR, 1.17; 95% CI (1.05, 1.30); p = 0.003], and cardiac block [HR, 1.15; 95% CI (1.02, 1.29); p = 0.023] risk among individuals with BMI 2 (Additional file 1: Figures S3, S4, S5), compared to individuals with BMI ≥ 25 kg/m2 (all Pinteraction Pinteraction = 0.010), but not for bradyarrhythmias (FDR-corrected Pinteraction = 0.072) or cardiac block (FDR-corrected Pinteraction = 0.084). The differential association patterns according to BMI strata are visually depicted in Fig. 4, suggesting a potentially stronger negative association between TTR levels and SVA, bradyarrhythmias, and cardiac block risk among individuals with lower BMI (2), as evidenced by steeper negative slopes in this subgroup. No significant interaction of BMI was observed for the association between TTR and VA, either before (Pinteraction = 0.161) or after FDR correction (FDR-corrected Pinteraction = 0.478; Fig. 4E and Additional file 1: Fig. S6). Interaction plots of dietary retinol intake and TTR levels with cardiac arrhythmias are presented in Additional file 1: Fig. S7, suggesting no significant interaction effects. In addition, all sensitivity analyses yielded results consistent with the primary findings (Additional file 1: Tables S5 and S6).
The association between TTR variants with arrhythmia outcomes
A total of 469,835 individuals were included in the genetic analysis (Additional file 1: Table S7). Consistent with prior report [19], a TTR variant was identified in 564 participants (0.12%), including 473 (0.10%) with LP/P variants and 91 (0.02%) with VUS. The p.Val142Ile variant accounted for the majority of LP/P variants, presenting in 367 of 473 individuals (77.59%). Compared to noncarriers [0.0 (− 0.2, 0.2)], individuals with LP/P [− 0.5 (− 0.7, − 0.2)], p.Val142Ile [− 0.5 (− 0.7, − 0.3)], and non-Val142Ile variants [− 0.5 (− 0.7, − 0.1)] had a lower plasma TTR level (Additional file 1: Table S7).
After adjusting for potential confounders, compared to noncarriers, TTR LP/P carriers were at a higher risk of developing incident AF [HR, 1.54; 95% CI (1.03, 2.29); p = 0.034], bradyarrhythmias [HR, 1.80; 95% CI (1.20, 2.71); p = 0.005], and cardiac block [HR, 1.90; 95% CI (1.23, 2.95); p = 0.004], but not SVA [HR, 1.42; 95% CI (0.95, 2.12); p = 0.084] or VA [HR, 1.60; 95% CI (0.79, 3.25); p = 0.191] (Table 3). Further analyses classified LP/P variants into p.Val142Ile, and non-Val142Ile variants suggested that the associations between LP/P variants with cardiac arrhythmias were mainly driven by non-Val142Ile variants. Specifically, carriers of non-Val142Ile variants had significantly increased risks of incident AF [HR, 2.31; 95% CI (1.24, 4.29); p = 0.008], as well as secondary outcomes including SVA [HR, 2.15; 95% CI (1.16, 3.99); p = 0.016], bradyarrhythmias [HR, 2.48; 95% CI (1.24, 4.97); p = 0.010], and cardiac block [HR, 3.29; 95% CI (1.65, 6.59); p HR, 1.94; 95% CI (0.49, 7.77); p = 0.348). No significant associations were observed between p.Val142Ile and any arrhythmia outcome (all p > 0.05) (Table 3).
Table 3 The associations between TTR variants with incident arrhythmias