Heterogeneity of Cardiomyocyte Lipid Droplets and Their Pathophysiological Implications in Cardiovascular Diseases.

The adult heart relies on fatty acid β-oxidation for energy, and cardiomyocyte lipid droplets (CLDs) are central to myocardial lipid homeostasis. CLDs are now recognized to protect cardiomyocytes against lipotoxicity, endoplasmic reticulum (ER) stress, oxidative stress, and nutrient deprivation. Moreover, accumulating evidence suggests that CLDs within the same cardiomyocyte are not uniform but may exhibit heterogeneity in size, subcellular localization, protein composition, and metabolism. Here, we propose a conceptual framework that classifies CLD heterogeneity along three dimensions: morphology, organelle connectivity, and molecular composition. We first define the biological characteristics of CLDs and categorize their heterogeneity. We then discuss the molecular pathways maintaining this heterogeneity, their roles in the healthy heart, and their dysregulation in cardiovascular diseases. Finally, we review preclinical strategies targeting CLD heterogeneity and outline challenges and future directions for clinical translation. This framework integrates current evidence while acknowledging that direct molecular validation awaits future single-droplet omics technologies.