Abstract Body (Do not enter title and authors here): Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease driven by amyloid accumulation in the myocardial extracellular space. CMR-derived extracellular volume (ECV) mapping provides a robust means of quantifying infiltration. While current therapies aim to halt deposition, agents targeting amyloid removal are in development. Understanding the infiltration spectrum, including early or subtle disease, may refine treatment strategies and trial endpoints.

Aims
To characterise the spectrum of myocardial amyloid infiltration in ATTR-CM using CMR-derived ECV, assess its association with conventional markers and evaluate its prognostic significance.

Methods
We retrospectively analysed 1408 patients undergoing CMR at a national centre (2011-2024). Patients were classified as asymptomatic carriers, non-cardiac ATTR, early or overt cardiomyopathy. For analysis, patients were stratified by ECV into five categories: no infiltration (0.20–0.29), mild (0.30–0.39), moderate (0.40–0.49), moderate-to-severe (0.50–0.59), and severe (≥0.60). Correlations between ECV and clinical markers (NAC stage, NT-proBNP, troponin, DPD grade, septal thickness, GLS) were assessed. Prognostic significance of ECV-categories was assessed using multivariable Cox models.

Results
ECV increased progressively across the ATTR spectrum (median 0.28 in carriers to 0.57 in overt disease), showing moderate correlation with all clinical markers (ρ range=0.57-0.61). However, individual-level discordance was marked: 24% of patients with NT-proBNP <500pg/mL and 49% of NAC stage I had at least moderate infiltration. In the lowest troponin and septal thickness tertiles, 32% and 34% had at least moderate infiltration. In multivariable analysis, ECV independently predicted all-cause mortality (HR per 0.10 increase: 1.14; 95% CI: 1.03–1.25; p=0.012), with risk rising notably above an ECV threshold of 0.43 on cubic spline modelling.

Conclusion
CMR-derived ECV provides a direct, continuous, and quantitative measure of myocardial amyloid burden, enhancing risk stratification beyond conventional staging. Substantial infiltration was often present in patients with low symptom burden or biomarker levels, highlighting limitations of current clinical frameworks. These findings support integrating ECV into routine clinical assessment to guide treatment—particularly when weighing stabilisers vs amyloid-removal therapies—and highlight its potential as a surrogate endpoint for amyloid-clearing trials.