A Study On The Effect Of PFO Closure On Cerebral Autoregulation In Migraineurs With PFO And The Underlying Mechanism

Part one Characteristics of cerebral autoregulation in migraineurs with PFOBackground and objective: A number of studies have provided substantial evidence for a strong relationship in patent foramen ovale(PFO),migraine and cryptogenic stroke.However,the underlying mechanism is largely unknown.We previously found that cerebral autoregulation(CA)was impaired in migraineurs with PFO,thus CA impairment may be another mechanism underlying PFO and cryptogenic stroke in addition to paradoxical embolization.In this section,we aimed to investigate the characteristics of CA in migraineurs with PFO,in order to provide new evidence for the link between PFO and cryptogenic stroke.Methods: In total,165 subjects were enrolled in the study,including 65 consecutive migraineurs with PFO(severe migraine,Headache Impact Test-6 score greater than 55;large right-to-left shunt,grade 2-3),fifty migraineurs without PFO during the same period,and fifty age and gender matched healthy controls.Non-invasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each patient by using transcranial Doppler and servo-controlled plethysmograph,respectively.Transfer function analysis was applied to derive autoregulatory parameters including phase difference(main evaluation index of CA),gain,autoregulation index,rate of recovery and coherence function in bilateral middle cerebral artery.Results: In this part of the study,all the data meet the inclusion criteria of the coherent function.The values of phase difference on the left(45.72 ± 12.75 degree)and right hemispheres(44.48 ± 12.12 degree)in migraineurs with PFO were significantly lower than the corresponding sides in both the migraineurs without PFO(53.57 ± 9.42 degree in the left and 53.61 ± 8.05 degree in the right)and the healthy controls(53.65 ± 14.11 degree in the left and 53.73 ± 13.11 degree in the right).There were no significant differences of bilateral phase difference between migraineurs without PFO group and healthy controls.The values of right gain in migraineurs without PFO group were significantly lower than the corresponding sides in healthy controls.There were no significant differences of autoregulation index and rate of recovery in each group.Conclusions: CA is significantly impaired in migraineurs with PFO whereas keeps intact in migraineurs without PFO.The impairment of CA in migraineurs with PFO may represent a potential mechanism linking PFO with cryptogenic stroke.Part two The effect of PFO closure on cerebral autoregulation in migraineurs with PFOBackground and objective: Recently,the CLOSE trial,long-term outcomes of RESPECT trial,and Gore REDUCE trial all reported the effectiveness of PFO closure in preventing cryptogenic stroke recurrence,though the mechanisms are largely unknown.In this section,we sought to further demonstrate whether CA improves after PFO closure,in order to provide new evidence for the prevention of cryptogenic stroke recurrence by PFO closure.Methods: All 45 migraineurs with PFO(a large right-to-left shunt)who received PFO closure were enrolled.All migraineurs with PFO received three CA measurements(< 24 hours before closure,< 48 hours after closure,and 30 days after closure).Noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each patient by using transcranial Doppler and servocontrolled plethysmograph,respectively.Transfer function analysis was applied to derive autoregulatory parameters including phase difference,gain,autoregulation index,rate of recovery and coherence function in bilateral middle cerebral artery.Results: In this part of the study,all the data meet the inclusion criteria of the coherent function.CA was impaired in migraineurs with PFO before closure(47.30 ± 12.83 degree in the left and 44.57 ± 12.24 degree in the right)compared with healthy controls(53.65±14.11 degree in the left and 53.73 ± 13.11 degree in the right,p < 0.05).After PFO closure,the impaired phase difference was largely resolved compared to before closure(53.27 ± 13.71 degree in the left and 54.49 ± 13.20 degree in the right,p < 0.05),and reached normal levels.These results remained unchanged after 1-month follow-up(52.33 ± 12.65 degree in the left and 52.18 ± 12.76 degree in the right).Autoregulation index in the left side increased temporarily after PFO closure and decreased to the preoperative level 30 days after closure.The gain and rate of recovery did not change after closure.Conclusions: Our results suggested CA was impaired in migraineurs with PFO,and PFO closure can improve impaired CA among migraineurs with PFO.Part three The mechanism of impaired cerebral autoregulation in migraineurs with PFO and the effect of PFO closure on related blood biomarkersBackground and objective: Previously we showed that CA was impaired in migraineurs with PFO,and PFO closure can improve impaired CA in migraineurs with PFO.The mechanism needs to be further studied.Based on the regulatory mechanisms of cerebral autoregulation(including endothelial function,myogenic responses,sympathetic control,and cerebral metabolism),in this section,we aimed to investigate whether the mechanism of CA impairment is caused by the changes of substances levels in arterial blood,and whether the mechanism by which PFO closure improves CA is due to it blocks the right to left shunt and changes the level of these substances in arterial blood that cause CA impairment.Methods: All 45 consecutive migraineurs with PFO(a large right-to-left shunt)who received PFO closure were enrolled.Arterial blood was collected in 45 migraineurs with PFO before and 10 minutes after surgery,as well as in 45 migraineurs without PFO group and 46 healthy controls.Human cytokine antibody array or targeted metabolomics were used to analyze the following blood biomarkers levels:(1)Endothelial-related biomarkers,including interleukin-1?(L-1?),macrophage inflammatory protein-1?(MIP-1?),matrix metallopeptidase-9(MMP-9),vascular endothelial growth factor-A(VEGF-A),vascular endothelial-cadherin(VE-Cadherin),angiogenin and tissue-type plasminogen activator(t-PA).(2)Myogenic responsesrelated biomarkers,including kallikrein,platelet-derived growth factor-BB(PDGFBB),renin and angiotensinogen.(3)Sympathetic control/cerebral metabolism-related biomarkers,including serotonin and ?-aminobutyric acid(GABA).Results:(1)The levels of VEGF-A and t-PA in migraineurs with PFO group were significantly lower in arterial blood before closure than healthy controls,and did not changed immediately after closure.There were no significant differences of the levels of MMP-9,MIP-1?,IL-1?,VE-Cadherin and angiogenin between migraineurs with PFO group and healthy controls.There were no significant differences of the levels of VEGF-A,t-PA,MMP-9,MIP-1?,IL-1?,VE-Cadherin and angiogenin between migraineurs without PFO group and healthy controls.(2)The level of kallikrein was significantly lower whereas the level of PDGF-BB was significantly higher in migraineurs with PFO group before closure than healthy controls,and the PDGF-BB decreased significantly immediately after PFO closure.There were no significant differences of the levels of renin and angiotensinogen between migraineurs with PFO group and healthy controls.The level of PDGF-BB was significantly lower in migraineurs without PFO group than healthy controls.There were no significant differences of the levels of kallikrein,renin and angiotensinogen between migraineurs without PFO group and healthy controls.(3)The level of GABA was significantly higher in migraineurs with PFO group before closure than healthy controls,and did not change immediately after closure.There were no significant differences of the level of serotonin between migraineurs with PFO group and healthy controls.There were no significant differences of the levels of serotonin and GABA between migraineurs without PFO group and healthy controls.Conclusions: The abnormal levels of VEGF-A,t-PA,kallikrein,PDGF-BB and GABA may contribute to CA impairment in migraine patients with PFO.PFO closure can immediately reduce the PDGF-BB level,which may be one of the important mechanisms of CA improvement.