Peroxisome proliferator-activated receptor-α activation attenuates susceptibility to postoperative atrial fibrillation.

BACKGROUND

Postoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery and is associated with adverse outcomes. Peroxisome proliferator-activated receptor-α (PPAR-α) is a key regulator of cardiac energy metabolism, but its role in POAF remains unclear. This study aimed to determine whether downregulation of the PPAR-α pathway contributes to POAF-related metabolic remodeling and whether pharmacologic activation of PPAR-α attenuates susceptibility to POAF.

METHODS

Thirty Sprague-Dawley rats were randomized into Sham, atrial fibrillation (AF; sterile pericarditis) and PPAR-α agonist (WY-14643) groups. Atrial and atrioventricular effective refractory periods (AERP, AVERP), AF inducibility and AF duration were measured, and atrial tissue underwent histological and molecular analyses. HL-1 atrial cardiomyocytes were allocated to Blank, pacing, PPAR-α agonist (GW7647) and inhibitor (GW6471) groups to validate PPAR-α-related metabolic changes in vitro. Sixty cardiac surgery patients with preoperative sinus rhythm (SR) were classified into POAF and SR groups based on new-onset AF within 7 days, and postoperative plasma and right atrial appendage samples were analyzed for Malonyl-CoA, oxidative stress indices and PPAR-α pathway proteins.

RESULTS

In rats, sterile pericarditis shortened atrial and atrioventricular refractory periods, increased AF inducibility, elevated Malonyl-CoA and reactive oxygen species (ROS) and induced atrial glycogen and lipid deposition; WY-14643 largely reversed these functional and metabolic changes and normalized PPAR-α/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and key lipid and glucose metabolism proteins. In HL-1 cells, rapid pacing or pharmacologic inhibition of PPAR-α reproduced pathway suppression and metabolic stress, whereas PPAR-α activation normalized metabolic markers and reduced Malonyl-CoA and oxidative stress. Clinically, POAF patients showed higher Malonyl-CoA and oxidative stress, lower antioxidant capacity, greater atrial glycogen and lipid accumulation, and a similar pattern of reduced PPAR-α/PGC-1α and fatty-acid oxidation proteins with increased sterol regulatory element-binding protein 1 (SREBP1) and pyruvate dehydrogenase kinase 4 (PDK4) compared with SR patients.

CONCLUSIONS

PPAR-α pathway downregulation is associated with disturbed cardiac lipid and glucose metabolism, mitochondrial dysfunction and an arrhythmogenic atrial substrate, increasing susceptibility to POAF. Consistent findings in animal, cellular and clinical settings suggest that pharmacologic activation of PPAR-α may be a promising strategy for POAF prevention.