Retrospective study links PFO closure to migraine relief and protein shifts

Patients with patent foramen ovale and migraine who underwent transcatheter closure experienced greater improvement in headache severity, disability and quality-of-life measures than patients who received standard medical therapy in a single-center retrospective cohort study. At 12 months, 55 of 58 patients in the closure group, or 94.83%, met the study’s criteria for effective treatment, compared with 36 of 49 patients, or 73.47%, in the medical-therapy group, a statistically significant difference (P = 0.003). Small exploratory proteomic and metabolomic analyses also identified changes after closure, but the study design cannot establish that the procedure caused the molecular differences or that they mediated symptom improvement.

The research, published in Frontiers in Cardiovascular Medicine on 20 October 2026, included 107 adults treated at Shanghai Changzheng Hospital between January 2023 and January 2026. All participants had migraine diagnosed under International Classification of Headache Disorders criteria and a patent foramen ovale with right-to-left shunting confirmed by cardiac imaging. The closure group contained 58 patients who received a transcatheter occluder, while the control group comprised 49 patients who received standard medical therapy without closure. Follow-up assessments covered headache episodes, pain intensity, migraine impact, disability, quality of life and depressive symptoms at one week and at 1, 3, 6, 9 and 12 months. Overall follow-up was complete through six months, with 105 of 107 patients, or 98.13%, assessed at 12 months.

The groups had similar distributions of sex, age and several recorded clinical characteristics, but important differences remained. Every patient in the closure group had a moderate or large right-to-left shunt: 38 were classified as large and 20 as moderate. The control group had 37 small and 12 moderate shunts and no large shunts. The closure group also began with greater headache severity, averaging 6.20 on the Visual Analogue Scale compared with 4.59 in controls. Because these baseline differences could affect raw follow-up scores, the investigators compared pre-to-post changes and performed multivariable regression adjusting for age, sex, baseline shunt grade and migraine subtype. Migraine with aura was present in 38 of 58 closure patients and 32 of 49 controls.

Headache severity improved more in the closure group at every follow-up assessment. The mean reduction in Visual Analogue Scale score was 3.28 points at one week in the closure group, compared with 0.92 points in controls. At 12 months, the corresponding reductions were 3.48 and 0.94 points, with P values below 0.001 for the intergroup comparisons at all measured time points. The closure group also had greater changes in Headache Impact Test, Migraine Disability Assessment, Migraine-Specific Quality of Life Questionnaire and Beck Depression Inventory-II scores, with every reported intergroup comparison yielding P values below 0.001. In the adjusted model, closure was associated with 2.86 additional points of 12-month Visual Analogue Scale improvement, with a 95% confidence interval of 1.92 to 3.80, after accounting for the measured covariates.

Patients with large shunts appeared to have greater improvement than those with moderate shunts. At 12 months, Visual Analogue Scale improvement averaged 4.12 points among the 38 closure patients with large right-to-left shunts and 2.86 points among the 20 with moderate shunts, a difference with P = 0.032. This subgroup observation included only 20 participants in the moderate-shunt category and had no corresponding control-group comparison, so it does not establish that shunt size determines who benefits. The study’s efficacy categories were based primarily on Visual Analogue Scale change: a reduction of at least five points or a final score of zero was classified as markedly effective, any reduction without reaching those thresholds as effective, and no reduction or an increase as ineffective. At 12 months, 37 closure patients were markedly effective, 18 were effective and three were ineffective, compared with 10, 26 and 13, respectively, in controls. The markedly effective and ineffective distributions differed significantly, while the difference in the effective category did not.

Blood-gas measurements in the closure group improved after the procedure. One month after closure, mean arterial partial pressure of oxygen, PaO₂, had risen from 82.86 to 85.84 mmHg, while mean arterial oxygen saturation, SaO₂, increased from 95.28% to 96.69%. Both changes were statistically significant, with P values below 0.01. Contrast-enhanced echocardiography performed one month after all 58 procedures showed complete closure of the foramen ovale without residual right-to-left shunting. The investigators considered the oxygenation findings consistent with elimination of intracardiac shunting, but the study did not provide an equivalent pretreatment blood-gas comparison for the medical-therapy group. The measurements therefore establish a temporal association within the closure group rather than demonstrating a causal pathway from shunt correction to headache improvement.

For the molecular analysis, the researchers selected five closure-group patients whose migraine had completely resolved after the procedure and compared their preoperative and one-month postoperative arterial plasma with samples from five age- and sex-matched healthy volunteers. Tandem mass-tag labeling and liquid chromatography-tandem mass spectrometry identified approximately 790 proteins. Before closure, the patient samples separated from healthy controls in principal-component analysis, and the preoperative and postoperative patient samples also showed some separation. Eighteen proteins met the study’s differential-expression threshold when preoperative and postoperative patient samples were compared. Myeloperoxidase, lysozyme C and heat shock protein 60 were described as inflammation- and oxidative-stress-related proteins whose expression was lower after closure; the findings do not demonstrate a direct reduction in oxidative stress itself.

Gene Ontology analysis of proteins that differed before and after closure identified enrichment in inflammatory-response regulation, response to oxidative stress, bacterial defense, gluconeogenesis and cellular responses to amino acids. Cellular annotations included extracellular exosomes, extracellular space, azurophil granule lumens and secretory granules, which the authors associated with immune-cell activation. Postoperative samples also showed relative increases in proteins involved in vascular or extracellular-matrix functions, including angiotensin-converting enzyme, collagen alpha-1(VI) chain and integrin alpha-2. Untargeted metabolomics identified differences in dopamine, L-proline, L-tyrosine, D-proline, acetylcarnitine and galactitol between post-closure patients and healthy controls, with pathway signals involving protein digestion and absorption, metabolism, transporter activity, and arginine and proline metabolism. These exploratory signals were not independently tested as predictive biomarkers, and the study did not show that they mediated the observed headache improvement.

Procedure-related outcomes were reassuring but remain limited by the small sample. Eight patients reported palpitations after activity and two reported postoperative chest tightness. Two patients developed new-onset atrial fibrillation, an incidence of 3.4%; both spontaneously returned to sinus rhythm and had no recurrence during the 12-month study period. No cardiac tamponade, device migration or embolization, thrombosis, infection or arteriovenous fistula occurred. The study’s principal limitations were its retrospective, single-center design, treatment-related differences in shunt severity and baseline symptoms, differing age eligibility ranges, reliance on self-reported headache outcomes and incomplete long-term imaging follow-up. The proteomic analysis included only five patients and five controls, healthy controls were not all screened by transesophageal echocardiography, and the direction of causality between the molecular changes, oxygenation and symptoms remains unresolved. The authors therefore describe the results as preliminary and say that larger prospective cohorts and randomized trials are needed before PFO closure can be considered a standard treatment for migraine or the candidate proteins can guide patient selection.

Subject of Research: Clinical outcomes and exploratory blood-protein changes associated with patent foramen ovale closure in patients with migraine

Article Title: Preliminary exploration of the pathogenesis of patent foramen ovale-related migraine and efficacy analysis of PFO closure

Article References: Ji, M., Xu, J., Luo, C., Gao, M., Pu, W., Peng, H., & Xiao, J. (2026). Preliminary exploration of the pathogenesis of patent foramen ovale-related migraine and efficacy analysis of PFO closure. Frontiers in Cardiovascular Medicine, 13, Article 1928840. https://doi.org/10.3389/fcvm.2026.1928840

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1928840

Keywords: patent foramen ovale, migraine, transcatheter closure, right-to-left shunt, retrospective cohort, plasma proteomics, arterial oxygenation, migraine with aura, inflammation, oxidative stress, Preliminary, exploration