Abstract
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.