The role of macrophages and mitochondrial homeostasis in aging-related cardiac dysfunction and atrial fibrillation

Cardiovascular disease, including atrial fibrillation (AF) and heart failure (HF), is strongly associated with aging. However, the molecular and cellular mechanisms by which aging promotes cardiac dysfunction remain poorly understood. Recent studies have implicated macrophage dysfunction, including abnormal polarization and impaired mitochondrial homeostasis, as critical contributors to age-related cardiac dysfunction and AF development. We hypothesize that aging-induced macrophage alterations promote cardiac inflammation and mitochondrial injury, contributing to cardiac dysfunction and AF. This project aims to systematically investigate the effects of aging on cardiac macrophage phenotypes and their interaction with cardiomyocytes. Initially, macrophage numbers, polarization states, autophagy markers, and inflammation will be assessed in aging mouse models to evaluate their correlation with AF susceptibility and cardiac function. In vitro studies will use tachypaced atrial myocytes , which will be co-cultured with macrophages to analyze mitochondrial transfer and cardiomyocyte functional responses. Pharmacological modulation of macrophage functionwill be tested for therapeutic potential. Finally, findings will be validated in a HFmouse model, employing histology, echocardiography, Western blot, and ELISA. The overall study design and working hypothesis are illustrated in Figure 1. The study will provide novel mechanistic insights into macrophage-driven aging-related cardiac dysfunction and AF, and identify potential macrophage-targeted therapeutic strategies for AF and HF.