Cross-cutting circuits in heart failure with preserved ejection fraction: Integrating adipokine biology, mechanotransduction, and precision targeting.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure cases. However, its complex pathophysiology, which is characterized by bidirectional interactions among immune, metabolic, and mechanical pathways, has long resisted a simple explanation. Approach: Rather than listing parallel mechanisms, this review organizes recent breakthroughs around three cross-cutting frontiers: neuroimmune regulation, cell-type-specific metabolic reprogramming, and mechanotransduction. It then integrates these frontiers within the adipokine hypothesis. Key findings: Cardiac macrophage subset imbalance, myeloid fatty acid-driven inflammation, matrix stiffness-mediated feedforward loops, and adipokine imbalance have emerged as interconnected drivers of HFpEF. Conclusion: With the aid of multi-omics and machine learning, mapping these mechanistic dialogues onto phenotype-targeted precision therapy provides a roadmap for transforming HFpEF from a syndrome defined by ejection fraction into molecularly tractable endotypes.