Journal of the American College of Cardiology最新文献

Background: Stabilizers/silencers limit new transthyretin amyloid formation, whereas emerging agents aim to clear existing deposits. Cardiovascular magnetic resonance (CMR) extracellular volume (ECV) reflects myocardial amyloid and may provide a quantitative framework for therapeutic planning OBJECTIVES: The aim was to define calibrated ECV thresholds, evaluate their diagnostic and prognostic value, and explore how CMR-ECV could provide a quantitative framework for disease staging and therapeutic planning.

Methods: We studied 1,541 subjects undergoing CMR for transthyretin amyloidosis (ATTR) classified as TTR-variant carriers (n = 123), extracardiac ATTR (n = 41), early-stage ATTR-CM (n = 70), or overt ATTR-CM (n = 1,308). The endpoint was all-cause mortality.

Results: ECV was similar in carriers and extracardiac ATTR but rose from early-stage to ATTR-cardiomyopathy (CM). Associations with biomarkers, National Amyloidosis Centre (NAC) stage, Perugini grade, and echocardiographic measures were modest, with wide overlap. Diagnostic performance was excellent: ECV <30% excluded and ≥40% confirmed cardiac involvement, whereas 30% to 39% indicated early infiltration. Over a median follow-up of 2.8 years (IQR: 1.4-4.3 years), 612 patients (40%) died. Prognostically, ECV independently predicted mortality (HR: 1.22 per 10% increase; 95% CI: 1.10-1.34 per 10% increase; P < 0.001) after multivariable analysist. Stratifying patients by ECV categories (degree of infiltration: none <30%; mild = 30%-39%; moderate = 40%-49%; moderate-to-severe = 50%-59%; severe ≥60%) showed monotonic risk increase across categories. ECV retained prognostic value across hs-troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strata, Perugini grades 1 to 3, and left ventricular mass index (LVMI) tertiles, with steeper gradients in low-biomarker/low-LVMI strata.

Conclusions: ECV directly quantifies myocardial amyloid load and, for the first time, defines reproducible thresholds that stratify burden and refine risk prediction beyond stage, biomarkers, and imaging, providing a quantitative framework for staging and therapeutic planning in ATTR amyloidosis.

Background: Therapies for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), including transthyretin (TTR) stabilizers and silencers, have demonstrated mortality benefit in 3 randomized trials. However, the timing of this benefit-often appearing delayed-has been debated and has broad implications for clinical use and trial design.

Objectives: The purpose of this study was to evaluate the time course of mortality benefit with TTR stabilizers and silencers in ATTR-CM by estimating time-varying treatment effects across 3 randomized trials.

Methods: We extracted time-to-event mortality data from the published Kaplan-Meier curves of 3 ATTR-CM outcomes trials: ATTR-ACT (tafamidis), ATTRIBUTE-CM (acoramidis), and HELIOS-B (vutrisiran). Using flexible parametric survival models, we estimated instantaneous HRs and assessed the time-varying treatment effects across trials.

Results: Mortality curves in each ATTR-CM trial began to diverge between approximately 12 to 18 months after therapy initiation. Instantaneous HRs showed consistent time-varying treatment effects across trials (P = 0.96), with a pooled model confirming a delayed but progressively strengthening benefit (P for treatment effect < 0.001; P for time interaction < 0.001). No significant differences were found between the 3 trials in the instantaneous HRs with widely overlapping CIs. We estimate that the treatment effect HR for mortality drops below 0.80 around 15 months (95% CI: 10-19) after randomization and continues to strengthen throughout follow-up.

Conclusions: TTR silencers and stabilizers in ATTR-CM confer a delayed but consistent mortality benefit with no significant differences observed between the 3 major trials. This uniform pattern may reflect a shared mechanism of action-reducing new amyloid deposition rather than reversing established disease-and may underscore the importance of early treatment initiation and adequate trial duration to capture delayed mortality effects. (ATTR-ACT [Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; NCT01994889]; ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy; NCT03860935]; and HELIOS-B [A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149]).