Mechanical dispersion and ventricular arrhythmia burden in wild-type transthyretin cardiomyopathy

Background Wild-type transthyretin cardiomyopathy (ATTRwt) is associated with a high prevalence of ventricular arrhythmias (VAs), although mechanisms linking myocardial dysfunction and arrhythmic burden remain unclear. Mechanical dispersion (MD), a strain-derived parameter reflecting temporal heterogeneity of left ventricular contraction, has been associated with myocardial heterogeneity and arrhythmic risk in other cardiomyopathies, reflecting multifactorial mechanisms, but its relationship with VAs and disease severity in ATTRwt remains incompletely defined. Purpose To evaluate the association between left ventricular MD, VA burden and disease severity in ATTRwt CM. Methods This observational study conducted at our university medical center, a tertiary referral centre for amyloidosis, included ATTRwt patients enrolled in the iNERVE cohort (substudy of iCARE) between Aug-2021 and Feb-2026. Patient underwent, in the context of a broad clinical and imaging assessment, echocardiography with speckle-tracking strain analysis and 24h Holter monitoring. All patients were tafamidis-naïve at baseline, and underwent a FU assessment after 1 year therapy. MD was defined as the standard deviation of time to peak longitudinal strain across LV segments. The primary endpoint was ventricular arrhythmia burden, defined as ventricular runs + VT-NSVT episodes/24 h. Associations were analysed using negative binomial regression. Patients were stratified according to the cohort median MD to explore phenotype differences. Results Forty patients were analysed (median age 78 y, 90% male). Baseline MD was 78.1 ms [68.9–119.6], GLS −9.8% [−12.3, −8.5], NT-proBNP 1822 pg/mL [1140–3638] and troponin T 41 ng/L [30.5–60]. Ventricular runs occurred in 60% and NSVT/VT episodes in 30%; median VT/NSVT burden was 3.5 [0–13]/24h. Complex ectopy was frequent (couplets 72.5%,bigeminy 70%). MD was associated with higher VA burden: each 10 ms MD increase was associated with a 39% higher expected VA burden [IRR 1.39 age adj (95% CI 1.12–1.73), p=0.003], remaining significant after adjusting for GLS and AF presence. MD was strongly associated with disease severity: correlated with Cheng stage (Gillmore-based p=0.025; Grogan-based, p=0.043). In median-split analyses, high-MD pts had more advanced Cheng stage (p=0.002 and 0.014) and higher NT-proBNP (1516.5 vs 2709, p=0.044) despite similar GLS values. At follow-up (N=37), no significant changes were observed in MD (80.7 ms, IQR 65.7–111, p=0.882), GLS (p=0.542), VA burden (runs 70.2%, VT/NSVT 64.9%, median VA burden 5.5/24h, p=0.922), and biomarkers (NT-proBNP, p=0.295 or troponin T, p=0.614), confirming clinical stabilization. Conclusions MD in ATTRwt CM is associated with VA burden, arrhythmic complexity and disease severity across stages, independent of GLS and AF presence, reflecting disease-related myocardial heterogeneity. Mechanical and arrhythmic parameters remained stable over FU.