Pathophysiological impact of one year of tafamidis in patients with transthyretin cardiac amyloidosis

Background Tafamidis stabilizes transthyretin (TTR) and improves clinical outcomes in transthyretin cardiac amyloidosis (ATTR-CM); however, its direct histopathological effects on human myocardial tissue remain unclear. Purpose This study aimed to evaluate the impact of one-year tafamidis therapy on myocardial amyloid deposition, fibrosis, inflammation, DNA damage, and left ventricular (LV) function. Methods Twelve patients with biopsy-proven ATTR-CM received tafamidis meglumine (80 mg daily) for one year. Serial endomyocardial biopsies were performed at baseline and after one year. Cardiac amyloid and collagen load were quantitatively assessed. Inflammatory cell infiltration (CD3-positive T lymphocytes and CD68-positive macrophages) and myocardial DNA damage (poly[ADP-ribose], PAR) were evaluated by immunohistochemistry. LV function including LV stiffness were assessed using invasive pressure-volume loop analysis, along with cardiac magnetic resonance imaging and biomarker measurements. Results After one year of tafamidis therapy, cardiac amyloid load significantly decreased (42.2±19.4% to 35.9±18.5%, p=0.03), whereas cardiac collagen load remained unchanged. Inflammatory cell infiltration showed no significant change. In contrast, myocardial DNA damage significantly decreased, with a reduction in PAR-positive nuclei (11.6±4.5% to 6.8±2.8%, p=0.01). LV volumes, LV systolic function, and LV stiffness assessed by pressure-volume analysis remained stable, without evidence of deterioration. Conclusions After 1 year of tafamidis therapy, paired endomyocardial biopsies showed a lower myocardial amyloid area and fewer PAR-positive nuclei, without progression of fibrosis or deterioration of LV mechanical properties. These findings raise the possibility that tafamidis may be associated with myocardial stabilization and molecular-level improvement in ATTR-CM and should be interpreted as exploratory.