Electro-metabolic coupling in atrial fibrillation: A deeper understanding of the metabolic driver

Atrial fibrillation (AF), the most common sustained heart rhythm abnormality, disrupts the normal link between electrical activity and atrial muscle contraction; this disruption is termed "excitation-contraction uncoupling". It weakens atrial contractions and contributes to the development and persistence of AF. In addition to electrical dysfunction, AF is increasingly recognized as a metabolic disorder. Metabolic remodeling may reportedly precede electrophysiological, contractile, and structural changes in AF. Both clinical observations and experimental studies have underscored the critical importance of metabolic homeostasis, and its disturbance is considered a key initial factor in the development of AF. Research in this field has progressed, and a consensus has emerged that metabolic status (energy flux) and electrophysiological signaling (ion flux) are interactively regulated, highlighting the concept of "electro-metabolic coupling." Their uncoupling or decompensation constitutes a common pathological basis of AF. Despite growing recognition of the importance of metabolic balance, the role of electro-metabolic coupling in AF remains unclear. Thus, this review aimed to discuss 1) a comprehensive understanding of electro-metabolic alterations post-AF, 2) the pivotal role of metabolic homeostasis in AF pathogenesis, and 3) the mutual regulation of electro-metabolic signaling, along with potential therapeutic strategies targeting these imbalances.