Effects of patent foramen ovale in migraine: a metabolomics-based study.

Patent foramen ovale (PFO), a cardiac anatomical anomaly inducing abnormal haemodynamics, leads to a paradoxical bypass of the pulmonary circulation. PFO closure might alleviate migraines; however, clinical evidence and basic experiments for the relationship are lacking. To explore the effect of PFO on migraine, 371 migraineurs finishing blood tests and contrast transthoracic echocardiography for the detection of PFO were prospectively included. Multivariate regression analysis revealed that PFO was independently associated with aura, and lower cystatin-C (cys-C) and calcium levels. Among them, patients with PFO who underwent percutaneous PFO closure were continuously followed up 1 year after the operation. The intensity of migraine was significantly relieved and the levels of cys-C and calcium increased after PFO closure. Untargeted and targeted metabolomics of plasma from migraineurs before and after PFO closure revealed that 5-HT and glutathione (GSH) metabolites were differentially expressed after PFO closure. The differential metabolites were then validated in the plasma and brain tissues of PFO mouse models by LC-MS/MS analysis. Desorption electrospray ionization mass imaging demonstrated that these metabolic alterations occurred mainly in the posterior cerebral cortex. Collectively, aura, cys-C and calcium could be biomarkers of migraineurs with PFO. PFO might have an impact on the posterior head associated with the regulation of 5-HT and GSH. PFO closure might relieve migraine by improving 5-HT clearance metabolism and ameliorating redox reactions. Our results may provide evidence for an indication of PFO closure in migraine and support the related potential mechanism. KEY POINTS: Aura, and levels of cystatin-C and calcium are biomarkers of migraineurs with a patent foramen ovale (PFO). The clearance of pulmonary metabolism of 5-HT and deoxygenated blood might be the reason for the improvement of migraine symptoms in patients with PFO. The posterior region of the brain is the main area responsible for PFO-induced migraine.