In this week's Editor's Page, Dr. Harlan Krumholz introduces Dr. Milton Packer's adipokine hypothesis, which proposes that dysfunctional visceral fat and the adipokines it secretes are central to the development of heart failure with preserved ejection fraction (HFpEF). This framework suggests that the benefits of therapies like GLP-1 receptor agonists and SGLT2 inhibitors may stem partly from restoring balance in adipose–cardiac signaling, offering a biologically grounded model for a condition long marked by therapeutic frustration. While the hypothesis is ambitious and unproven, it provides a coherent structure for future research and exemplifies how bold, integrative thinking can advance medical understanding.