Extracellular volume from cardiac magnetic resonance reflects histologically quantified myocardial amyloid load: stereological validation in transthyretin amyloidosis

Background Extracellular volume (ECV) derived from cardiovascular magnetic resonance (CMR) is widely used as a noninvasive marker of myocardial amyloid burden in transthyretin amyloidosis cardiomyopathy (ATTR-CM). However, direct validation of ECV against histologically quantified myocardial amyloid load remains limited. Purpose To evaluate whether ECV reflects histologically quantified myocardial amyloid load in patients with ATTR-CM. Methods A cross-sectional study including wild-type ATTR-CM (ATTRwt-CM) patients who underwent both right ventricular endomyocardial biopsy and CMR. Amyloid load was quantified on 2-4 Congo Red-stained paraffin-embedded biopsy samples using design-based stereology with systematic uniform random sampling and calculated as the weighted area fraction of amyloid deposition according to point-counting principles. ECV was calculated from native and post-contrast T1 mapping as a global myocardial measure. Associations between histologically quantified amyloid load and ECV were assessed using simple linear regression and Spearman’s rank correlation. Results A total of 50 patients were included (median age 80 (IQR 75-84) years, 98% male). The median histologically quantified myocardial amyloid load was 15.2% (IQR 7.1-24.6). Patients with a myocardial amyloid load above the median had higher NT-proBNP levels, greater left ventricular mass, and higher ECV compared with those below the median. Myocardial amyloid load demonstrated a strong positive correlation with ECV (Spearman ρ = 0.714, p < 0.001). In linear regression analysis, histologically quantified amyloid load was associated with ECV (β = 0.57, 95% CI 0.40–0.74, p < 0.001), explaining 49% of the variance in ECV (R2 = 0.49). Conclusion ECV is strongly associated with histologically quantified myocardial amyloid load in ATTRwt-CM. These findings provide biological validation of ECV as a non-invasive marker of myocardial amyloid burden.