Abstract Body: Background: Atrial fibrillation (AF) is sustained by progressive atrial fibrosis, yet mechanisms that endogenously constrain remodeling remain undefined. GDF11 attenuates cardiac hypertrophy and fibrosis in multiple stress models but requires BMP1/TLL1-mediated cleavage for activation. In our recently published study, only activated GDF11/8 subforms, not total levels, predicted cardiovascular events and mortality (HR 0.43 - HR 0.33), establishing activation-state biology as clinically relevant. We hypothesized that impaired proteolytic activation removes a key checkpoint limiting atrial fibrosis.
Methods: Activated GDF11/8 levels were analyzed in ARIC (aging-related vulnerability) and CRIC (CKD stress predisposition) for associations with incident AF and left atrial enlargement. Mechanistic testing employed tamoxifen-inducible Bmp1/Tll1 deletion followed by AngII infusion (2mg/kg/day - 14days). Remodeling was quantified by histological fibrosis and hypertrophy. Recombinant (r)GDF11 (1mg/kg) was administered in AngII-treated wild-type mice.
Results: Reduced TLD-activated GDF11/8 independently predicted incident AF and progressive atrial enlargement (adjusted HR 0.82 per MAD - q=3.51×10^-3). Genetic loss of TLD activity amplified AngII-induced atrial hypertrophy and fibrosis with enhanced myofibroblast activation. Conversely, administration of rGDF11 in AngII-treated wild-type mice significantly attenuated atrial fibrosis and hypertrophy compared to vehicle-treated controls.
Conclusions: Proteolytic activation of GDF11 constitutes a regulatory checkpoint governing atrial fibrosis. Convergent human and mechanistic data demonstrate that impaired activation amplifies structural remodeling, whereas restoration restrains progression. Activation-state control, rather than ligand abundance, emerges as a therapeutic principle in AF.