Migraine With Aura and Patent Foramen Ovale: Identification of Biomarkers to Select Patients In Whom Intervention Would Be Beneficial (MANET)

Sponsor

Centro Cardiologico Monzino (Other)

Overall Status

Recruiting

CT.gov ID

NCT06046508

Collaborator

IRCCS Policlinico S. Donato (Other), Università di Cagliari (Other), Federico II University (Other)

120

Enrollment

Locations

22.5

Anticipated Duration (Months)

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter prospective observational study aimed to asses whether a specific prothrombotic platelet phenotype can discern migraine patients with PFO (patent forame ovale)

related symptoms from patients with incidental PFO. The study will also explore additional distinguishing features of causal and incidental PFO using a metabolomics approach. It involves the enrollment of well-characterized patient cohorts and an ex vivo approach using comparative cell biology models that reproduce the most critical aspects of the clinical scenario.

Condition or Disease	Intervention/Treatment	Phase
Migraine Headache PFO - Patent Foramen Ovale	Other: blood samples collection

Detailed Description

Patients with PFO, who meet all the inclusion and none of the exclusion criteria, will be enrolled in the study. Patients will undergo percutaneous correction of PFO and the following evaluations as clinical practice:

thrombophilic screening (factor V and II and MTHFR gene mutation); sampling for homocysteine, Protein C (Prot C), Protein S (Prot S) and antithrombin III assay;
anatomic evaluation of the SIA (Saccular intracranial aneurysm) by color-doppler TT echocardiogram and intracardiac ultrasound for definition of the anatomy of the fossa ovalis: tunneled appearance; absence of SIA aneurysm; bulging of the SIA; convex right/left SIA aneurysm;
quantification of right-left intracardiac shunt by CT doppler;
classification of migraine according to Anzola scale at baseline visit, post PFO correction, at follow-up at 6 and 12 months.

For the purpose of the study, blood sampling will be performed for evaluation of platelet reactivity; oxidative stress, aggregability, and deformability of red blood cells; and isolation of Endothelial Colony Forming Cells (ECFCs) for analysis of endothelial function. The latter in particular will be evaluated in comparison with the endothelial function of 30 subjects without known disease with age > 18 years, enrolled as a control group.

All analyses will be performed before PFO correction and 180 days after surgery.

Study Design

Study Type:

Observational

Anticipated Enrollment :

120 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Migraine With Aura and Causal or Incidental Patent Foramen Ovale (PFO): Identification of Biomarker(s) to Select Patients Who Would Most Benefit From PFO Closure. The MANET Study

Actual Study Start Date :

May 18, 2023

Anticipated Primary Completion Date :

Apr 1, 2025

Anticipated Study Completion Date :

Apr 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Sigle arm study Patients with migraine headache with aura (MHA), patent foramen ovale (PFO) and previous neurological event (transient ischemic attack -TIA- or stroke) with clinical indication for percutaneous correction of the defect according to guidelines will be enrolled	Other: blood samples collection patients, who meet all the inclusion criteria and none of the exclusion criteria, will be enrolled and they will perform a blood withdrawal before PFO correction and 180 days after the intervention

Arm

Intervention/Treatment

Sigle arm study

Patients with migraine headache with aura (MHA), patent foramen ovale (PFO) and previous neurological event (transient ischemic attack -TIA- or stroke) with clinical indication for percutaneous correction of the defect according to guidelines will be enrolled

Other: blood samples collection

patients, who meet all the inclusion criteria and none of the exclusion criteria, will be enrolled and they will perform a blood withdrawal before PFO correction and 180 days after the intervention

Outcome Measures

Primary Outcome Measures

Platelet activation [through study completion, an average of 2 years]
Fresh whole blood will be stained for tissue factor (TF) expression, platelet activation markers [P-selectin and activated glycoprotein IIbIIIa] and annexinV binding to phosphatidylserine (PS). Flow cytometry analysis will be performed on fixed samples. Platelet procoagulant potential will be assessed by thrombin generation assay. The CAT assay (Chloramphenico Acetyltransferase) lwill be performed in the presence of a neutralizing anti-Tisse Factor (aTF) antibody (Ab) to assess the contribution of TF, and by adding an excess of exogenous phospholipids.
Thrombin generation [through study completion, an average of 2 years]
Flow cytometry MV characterization will be performed on stored patients' plasma samples. On the same plasma samples, MV procoagulant potential will be assessed by thrombin generation assay.
Quantification of the oxidative status [through study completion, an average of 2 years]
RBC (red blood cells) deformability and aggregability, generation of oxygen radicals in RBC and platelets of the overall enrolled population will be analyzed at T0 and at T1. Systemic redox status will be quantified by evaluating concentrations of both reduced glutathione (GSH) and its oxidized form GSSG (oxidized glutathione) on stored samples.
Untargeted metabolomics [through study completion, an average of 2 years]
The metabolomic patterns of plasma, urine and platelets/ECFC (endothelial-colony forming cells) of the enrolled population will be investigated by a combined use of spectroscopy and multivariate and univariate statistical tools in order to identify the molecular fingerprint that could build a score able to identify patients with incidental PFO.

Secondary Outcome Measures

Elucidate whether mechanical stress related to the right-to-left shunt may influence Erythrocyte behavior affecting in turn oxidative stress status [through study completion, an average of 2 years]
This will be accomplished ex vivo by using a microfluidic platform that recapitulates the specific shear stress profiles to which blood is exposed as it flows through the PFO
Assess whether a unique endothelial dysfunction profile identifies migraineurs with incidental PFO [through study completition, an average of 2 years]
Functional profiling will be carried out, by measuring proliferation, migration and in vitro angiogenesis. The pro-inflammatory and pro-thrombotic phenotype of the cells will be assessed using a panel of molecular markers. Platelet adhesion will be determined on resting and activated ECFC under flow conditions; thrombin generation will be measured using a cell-based assay.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

presence of PFO with right-left shunt at baseline > 10 MES and during Valsalva > 20 MES
previous Stroke or TIA
positive MRI for ischemic outcomes
SIA aneurysm or residual Chiari/Eustachian valve network
thrombophilic screening positivity (MTHFR/prot C/prot S)
cability to sign informed consent for study participation and adherence to planned clinical follow-ups

Exclusion Criteria:

paroxysmal/refractory atrial fibrillation
TSA vasculopathy
left ventricular ejection fraction <30%
moderate/severe mitral valve regurgitation
need for long-term anticoagulant therapy
allergy or intolerance to antiplatelet therapy
nickel allergy
severe chronic kidney disease (GFR < 30 mL/min)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IRCCS Policlinico San Donato	San Donato Milanese	Milan	Italy	20097
2	Università di Cagliari	Cagliari		Italy	09124
3	Azienda Ospedaliera Universitaria "Federico II"	Napoli		Italy	80131