PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. AF is uniquely associated with the development of heart failure with preserved ejection fraction (HFpEF). Both AF and HFpEF are associated with metabolic syndromes. Cardiac remodeling during HFpEF can be partially explained by changes in substrate utilization, AKT signaling, and enhanced insulin resistance. As a chaperon protein, FKBP5 is known to modulate the phosphorylation and activity of AKT via PHLPP. Mice that lack FKBP51 exhibited increased AKT activity and increased insulin resistance. The role of ‘FKBP5 – PHLPP – AKT’ signaling in the concomitant AF and HFpEF has not been reported previously. We recently have reported that the loss of FKBP5 can lead to cardiac fibrosis, atrial myopathy, and enhanced AF inducibility. Whether the increased AF susceptibility, due to the loss of FKBP5, can perpetuate the progression of HFpEF remains an open question. In this application, we will test the hypothesis that FKBP5 deficiency accelerates the progression of HFpEF by promoting the development of AF.