Cardiac Metabolism in Healthy, Senescent and Diseased States

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The healthy adult heart depends on flexible energy use, but a diseased or injured heart is associated with a loss of flexibility and metabolic remodeling. Since metabolism plays a central role in cardiac health and disease, there is a growing need to understand how metabolic reprogramming contributes to cardiac dysfunction and impaired CM maturation. Human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) are widely used as a platform to study human cardiac development and disease mechanisms. However, current models are limited by metabolic and structural immaturity. This review provides an overview of the dynamic shifts in cardiac metabolic states from fetal development to senescence, while delineating the metabolic signatures of healthy versus disease states. These metabolic switches are orchestrated by a complex interplay of upstream signals driven by variations in substrate availability, post-translational modifications and key transcriptional regulatory networks, which ultimately regulate downstream cardiac remodeling and pathological cascades. As cardiac metabolic function is affected by a coordinated multicellular network, this review also includes the metabolic crosstalk between CMs and non-CMs, including fibroblasts, endothelial cells and immune cells. In addition, various strategies to further mature hiPSC-CMs are summarized to enhance their metabolic profiles. Investigating cardiac metabolic shifts bridges developmental biology, stem cell biology, and regenerative cardiology by revealing how energy metabolism governs cellular identity, maturation, and regenerative potential. These insights are essential for improving stem-cell-derived CMs for disease modeling, drug discovery, and heart repair.