Histopathological myocardial fibrosis associated with amyloid burden predicts cardiovascular events in transthyretin cardiac amyloidosis
M Fujita, S Kobayashi, J Nawata, M Ishikawa, Y Nakashima, Y Nakamura, A Omuro, T Nanno, H Ishiguchi, T Fujimura, M SanoAbstract
Background
In transthyretin cardiac amyloidosis (ATTR-CM), myocardial transthyretin amyloid deposition causes progressive myocardial damage; however, the pathological mechanisms underlying myocardial injury and fibrosis remain incompletely understood. Cardiac magnetic resonance (CMR) imaging can assess myocardial amyloid burden, but distinguishing amyloid deposition from irreversible myocardial fibrosis remains challenging.
Purpose
This study aimed to investigate the relationships among histopathological ATTR amyloid burden, myocardial fibrosis, CMR parameters, and cardiovascular outcomes in patients with ATTR-CM.
Methods
We prospectively enrolled 29 consecutive patients with ATTR-CM diagnosed by right ventricular septal endomyocardial biopsy between January 2019 and July 2025. ATTR amyloid burden was quantified as the percentage area positive for anti-ATTR immunostaining (%ATTR, Fig1A). Myocardial interstitial fibrosis (%Fibrosis, Fig1A) was calculated as the Picrosirius red–positive area minus the %ATTR area. Associations between histopathological findings, clinical parameters, echocardiographic indices, 99mTc-pyrophosphate scintigraphy, and CMR parameters were evaluated. Primary outcome was defined as a composite endpoint of all-cause death or cardiovascular hospitalization.
Results
The median age was 77 years, median left ventricular ejection fraction was 50%, and median NT-proBNP level was 1966.5 pg/mL. %ATTR was positively correlated with %Fibrosis (r = 0.614, p = 0.0004, Fig1B) and inversely correlated with cardiomyocyte area (r = −0.769, p < 0.0001, Fig1B). Furthermore, extracellular volume fraction (ECV) on CMR was positively correlated with %ATTR (r = 0.558, p = 0.016, Fig2A) and %Fibrosis (r = 0.624, p = 0.0056, Fig2B). During a median follow-up of 405 days, 10 patients experienced cardiovascular events. In multivariable Cox hazard model analysis, %Fibrosis was an independent predictor of cardiovascular events (p = 0.032). Receiver operating characteristic analysis identified a %Fibrosis cut-off value of 10.64% (sensitivity = 0.70, specificity = 0.79, AUC = 0.795, Fig2C), and Kaplan-Meier analysis demonstrated that patients with higher %Fibrosis had a significantly increased risk of cardiovascular events (log-rank p = 0.020, Fig2D).
Conclusions
Histopathological ATTR amyloid burden is closely associated with myocardial interstitial fibrosis, suggesting that progressive amyloid deposition promotes fibrotic myocardial remodeling in ATTR-CM. CMR-derived ECV reflects both myocardial amyloid burden and fibrosis and provides clinically relevant pathological and prognostic information. These findings highlight the clinical utility of integrating histopathology and CMR for risk stratification and therapeutic decision-making in patients with ATTR-CM.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.