Researchers analyzed over 5,000 circulating proteins from two randomized rehabilitation trials in heart failure with preserved ejection fraction (HFpEF) patients, identifying specific protein networks that predict and mediate physical function improvements. The study revealed four key biological pathways—endothelial remodeling, mitochondrial metabolism, calcium handling, and immune modulation—that coordinate rehabilitation responses across heart, skeletal muscle, and brain tissues. Multi-protein signatures correlated with functional improvements and predicted outcomes in over 26,000 individuals. This systems-level approach represents a significant methodological advance in understanding how rehabilitation works at the molecular level in HFpEF, a condition affecting millions of older adults with limited treatment options. The identification of tissue-specific protein networks could enable precision medicine approaches to optimize rehabilitation protocols and identify patients most likely to benefit. However, the complexity of these multi-system interactions and the observational nature of protein associations require validation in independent cohorts. As a preprint awaiting peer review, these promising findings need confirmation before clinical translation, but the comprehensive approach offers unprecedented insights into the molecular machinery of physical recovery in cardiovascular disease.