Mechanics, inflammation, and metabolism as integrated drivers of heart failure

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Mechanical remodeling of the cardiac extracellular matrix (ECM) impairs cardiomyocyte contractility and causes cardiac stiffening. Chronic low-grade inflammation, often fueled by metabolic stress, is emerging as a central regulator of cardiac stiffening and HF. A central axis in this process is the dynamic crosstalk between immune cells, cardiac fibroblasts, and the altered mechanical and metabolic cues they sense under stress. These interactions govern ECM synthesis, crosslinking, and tissue stiffening, which simultaneously perpetuate inflammation and mechanical stress in a vicious cycle. This review provides a view on the implications of tissue mechanics on inflammation, metabolic regulation, and cellular crosstalk in HF, and how this interplay may be therapeutically modulated.