Mitochondrial damage mediates STING activation driving obesity-mediated atrial fibrillation

AIMS: Obesity is a significant risk factor for atrial fibrillation (AF), but the mechanisms by which obesity contributes to AF are not fully understood. Recent studies have indicated that the Stimulator of Interferon Genes (STING) signalling, mediated by mitochondrial damage, plays a crucial role in cardiac remodelling in various metabolic and cardiovascular diseases. This study aims to explore the role of STING in obesity-mediated AF and its potential mechanisms. METHODS AND RESULTS: In this study, rats were divided into four groups: two groups received tail vein injections of AAV9-cTnT-STING siRNA and were fed either a normal diet or a high-fat diet (HFD) for 12 weeks; the other two groups received injections of AAV9-cTnT-NC siRNA and were similarly fed either a normal diet or a HFD. The atrial STING signalling, AF vulnerability, electrical remodelling, and substrate remodelling were assessed in all groups. Results showed that the induction of AF was increased in obese rats, accompanied by severe mitochondrial damage and upregulation of the STING inflammatory signalling cascade. STING activation was associated with atrial fibrosis, cardiomyocyte apoptosis, and substrate remodelling, including alterations in the gap junction protein CX40 and ion channels. Additionally, STING was linked to excessive calcium transfer from the endoplasmic reticulum to the mitochondria. Knockdown of STING prevented AF vulnerability and both electrical and substrate remodelling in obese rats. CONCLUSION: Mitochondrial damage-mediated activation of the STING signalling pathway promotes obesity-induced atrial remodelling and the occurrence of AF.