Trajectory and prognostic significance of conduction system disease in cardiac transthyretin amyloidosis: a european multicenter cohort study

Background Conduction system disease (CSD) is highly prevalent in cardiac transthyretin amyloidosis (ATTR-CA), yet its progression and prognostic relevance in the era of disease-modifying therapy remain unclear. Purpose We investigated atrioventricular (AV) and intraventricular CSD in ATTR-CA and their association with clinical outcomes in a contemporary cohort. Methods This retrospective observational study included patients with ATTR-CA from 13 European amyloidosis referral centres. The primary endpoint was all-cause mortality. Secondary endpoints included new-onset AV block, new-onset intraventricular conduction delay (QRS ≥120 ms), and new permanent pacemaker implantation. Laboratory, echocardiographic, and ECG data were longitudinally assessed and outcomes censored at 6 years. Statistical analyses utilized multivariable Cox regression for mortality, Fine-Gray competing risk models for PM implantation accounting for death as a competing risk, and mixed-effects logistic regression to identify CSD predictors. Results We included 1034 patients with ATTR-CA (mean age 79 years, 86% male). Median follow-up was 25 months (IQR 14-39). At diagnosis, 55% had AV block of any degree and 29% QRS ≥120 ms. Baseline CSD was associated with advanced disease stage and severe structural remodeling. 12- and 24-month survival was 96% and 88% (Fig. 1). In univariate regression analysis, AV block > I. degree at diagnosis and QRS duration were not associated with increased mortality (HR 1.34, 95% CI 0.99–1.80, p=0.057, and HR 1.003, 95% CI 0.99–1.01, p=0.23). Age, genotype, and NAC stage predicted mortality in multivariate analysis. At diagnosis, 159 patients (15%) had a pacemaker for treatment of bradycardia due to CSD. Of 875 patients without pacemaker, 100 (11.4%) required implantation during follow-up (Fig. 2). QRS duration at baseline was the only predictor of pacemaker implantation in multivariable regression considering death as a competing risk (HR 1.85, 95% CI 1.41–2.42, p < 0.001). New-onset AV block of any degree not requiring pacemaker implantation occurred in 97 patients (n=296, 33%) and was associated with male sex (HR 2.46, 95% CI 1.21–5.02, p=0.01) and resting heart rate (HR 1.024, 95% CI 1.01–1.04, p=0.008). New-onset ventricular conduction delay (QRS ≥120 ms) was observed in 110 patients (n=650, 17%), and was significantly predicted by septal wall thickness and QRS duration at diagnosis (HR 1.07, 95% CI 1.00–1.15, p=0.046, and HR 1.07, 95% CI 1.05–1.09, p<0.001, respectively). Advanced electrical dyssynchrony (QRS>130ms) occurred in 8%. Conclusions In this contemporary ATTR-CA cohort, CSD was highly prevalent and progressive. Baseline AV block and QRS prolongation were not independently associated with mortality. These findings suggest that electrical remodeling reflects myocardial infiltration and underscore the importance of structured ECG monitoring to guide timely rhythm management or pacing strategies.Fig. 1.Survival probabilityFig. 2.PM implant. (death as competing risk)