Myocardial fibrosis in cardiac amyloidosis: evidence from left ventricular endomyocardial biopsies
A Aimo, V Musetti, V Castiglione, F Greco, Y F Ferrari Chen, G Vergaro, M Emdin, A PucciAbstract
Background
Treatment options for cardiac amyloidosis (CA) are rapidly expanding. Therapies that suppress further amyloid accumulation may enable partial amyloid reabsorption, and emerging monoclonal antibodies may further enhance amyloid clearance. In contrast, myocardial fibrosis, triggered by cardiac injury and amyloid deposition, may be less reversible. Fibrosis data in CA remain limited, often derived from explanted hearts; furthermore, many centers rely on right ventricular biopsy, potentially limiting tissue characterization. Better defining fibrosis in CA is important to refine expectations of complete versus partial functional recovery with amyloid-lowering therapies and to inform the potential role of adjunct therapies targeting profibrotic pathways.
Methods
We analyzed consecutive patients undergoing left ventricular (LV) endomyocardial biopsy for suspected CA at a tertiary referral center; patients with prior myocardial infarction were excluded. Histology quantified fibrosis and amyloid burden (both as percentage of tissue area), recorded amyloid localization, and measured inflammatory cell density. Extracellular volume (ECV) from cardiovascular magnetic resonance was also assessed.
Results
The cohort included 110 patients (median age 75 years, interquartile range [IQR] 69–80; 82% male); diagnoses were ATTR-CA in 63 (57%) and AL-CA in 47 (43%). Median fibrosis extent was 10% (IQR 5-15) in the whole cohort (AL-CA, 10% [5-15%]; ATTR-CA, 10% [5-18%]; p=0.640). Fibrosis was focal or plurifocal in both forms (AL-CA: 48% vs 52%; ATTR-CA: 60% vs 40%; p=0.30). Fibrosis did not correlate with total amyloid burden (Spearman rho=−0.12, p=0.23), but was higher in patients with interstitial amyloid localization (15% [10–25] vs 7% [5–10]; p<0.001). Fibrosis correlated with macrophage and T-cell density (AL-CA: CD68+ rho=0.332, p=0.028; CD3+ rho=0.340, p=0.022; ATTR-CA: CD68+ rho=0.408, p=0.002; CD3+ rho=0.342, p=0.015). In the subset with ECV (n=54; AL-CA n=31, ATTR-CA n=23), ECV tracked amyloid burden more closely than fibrosis (ECV vs amyloid rho=0.442, p=0.001; ECV vs fibrosis rho=0.225, p=0.105), driven primarily by ATTR-CA (ECV vs amyloid rho=0.528, p=0.010; ECV vs fibrosis rho=0.110, p=0.617). In AL-CA, ECV showed only borderline associations with both amyloid and fibrosis (rho=0.327, p=0.083; rho=0.344, p=0.063).
Conclusions
In a contemporary cohort with LV biopsy–proven CA, fibrosis is common and similar in AL- and ATTR-CA. Fibrosis is more closely related to interstitial amyloid accumulation and inflammatory infiltrates than to total amyloid burden, and CMR-derived ECV appears to track amyloid burden more than fibrosis, particularly in ATTR-CA. Together, these results support pursuing adjunct antifibrotic therapies and fibrosis-specific imaging to better estimate recovery potential and monitor myocardial remodeling after amyloid-removal therapies, rather than relying on ECV alone.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.