Adipocyte Extracellular Vesicle Mitochondrial Cargo is Linked to Cardiomyocyte Dysfunction in Type 2 Diabetes–Related Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent in type 2 diabetes (T2D), yet disease-modifying therapies remain limited. Here we identify an adipose-cardiac communication axis in which stressed adipocytes export extracellular vesicles (AdEVs) laden with oxidatively damaged mitochondrial proteins that are associated with impaired cardiomyocyte bioenergetics and increased apoptosis. Single-nucleus RNA-seq of human subcutaneous adipose tissue from patients with T2D-HFpEF revealed metabolic stress in adipocytes, characterized by enriched mitochondrial oxidative stress genes and reduced metabolic flux. The severely affected AD3 subpopulation exhibits mitochondrial impairments, potentially accompanied by increased AdEV release. In parallel, circulating AdEVs were elevated and their mitochondrial cargo showed greater oxidative modification; AdEV abundance tracked systemic protein carbonyls and clinical markers of cardiac load. In vitro, lipotoxic adipocytes released AdEVs enriched for mitochondrial components with increased protein carbonylation. When applied to human cardiomyocytes (AC16 and human induced pluripotent stem cell-derived cardiomyocytes), these AdEVs increased reactive oxygen species (ROS), dissipated mitochondrial membrane potential, fragmented mitochondrial networks, reduced oxygen consumption and ATP production, and activated intrinsic apoptosis and heart-failure marker expression. Inhibition of EV biogenesis (GW4869) or scavenging of mitochondrial ROS (Mito-TEMPO) blunted these effects. Collectively, our data support a model in which oxidatively modified mitochondrial cargo within AdEVs links adipose stress to cardiomyocyte dysfunction in T2D-HFpEF and suggest that AdEV release and mitochondrial ROS may represent tractable therapeutic targets.