Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction

Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in male HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic remodeling and cardiomyocyte-fibroblast communication can be corrected, constituting an alternative therapeutic strategy for HFpEF. Here, the authors show that suppression of FoxO1 signaling in HFpEF reduces arrhythmias by improving cardiac fibrosis and cardiomyocyte-fibroblast communication. These findings suggest that targeting FoxO1 signaling may serve as an anti-arrhythmic therapeutic strategy for HFpEF.