Macrophage‐Dependent Intercellular Crosstalk in Multiphenotypic Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is now recognized as a complex, multiphenotypic metabolic syndrome fueled by inflammation and metabolic dysregulation, rather than a single disease entity. Cardiac macrophages, as the most abundant immune cells in the heart, are emerging as central players in HFpEF pathogenesis by orchestrating intercellular crosstalk and driving maladaptive remodeling. This review delineates the intricate macrophage-dependent vicious cycle in HFpEF. We first elaborate on the heterogeneity of cardiac macrophages and the diverse clinical and preclinical phenotypes of HFpEF. We then synthesize evidence demonstrating how risk factors, like aging, cardiometabolic disease, and hypertension, induce profound phenotypic switching and functional reprogramming of macrophages across different HFpEF subtypes. Subsequently, we detail how these reprogrammed macrophages, in turn, propagate disease progression by promoting inflammation, fibrosis, and endothelial dysfunction through complex interactions with cardiomyocytes, fibroblasts, and other cellular components. Targeting specific macrophage subsets and their effector mechanisms presents a promising therapeutic strategy for mitigating the burden of this heterogeneous syndrome.