1、卵圆孔未闭封堵术：争论与发展May 9,2009Andrew D.Michaels,MD,MAS,FACC,FAHADirector,Cardiac Catheterization Laboratory and Interventional CardiologyUniversity of Utah,Salt Lake City,Utah胎儿循环胎儿期，氧合血液由脐静脉经下腔静脉进入右房血流由下腔静脉经过Eustachian 瓣流到卵圆窝.出生后房间隔发育宫内出生后Hagen,Scholz.Mayo Clin Proc 1984;59:17-20.人口的75 人口 的25%PFO相关临床综合症体
2、位相关呼吸困难 Platypnea orthodeoxia减压病/高原性肺水肿脑血管事件/TIA偏头痛Platypnoea Orthodeoxia罕见直立体位引起的呼吸困难，伴有低氧血症机制：右向左房间分流Aigner et al.Eur J Cardiothor Surg 2019;33:268.Medina et al.Circulation 2019;104:741.Platypnea Orthodeoxia1949年至今已有文献报道近100例 PFO 常伴有:主动脉瘤胸廓畸形肺切除术后约50例已接受封堵术减压病对230名 无症状潜水者进行研究27%有PFO需要减压舱治疗者:19%有PF
3、O2%无 PFOTorti et al.Eur Heart J 2019;25:1014-20.隐匿性脑卒中40岁男性，突发失语既往史无特殊.无明显脑卒中病因.TEE:发现房间隔瘤与 PFO.常见伴发症:50%隐匿性脑卒中患者有 PFO.推测机制:静脉血栓反常性体循环栓塞症.PFO 通道内原位血栓形成造成栓塞血栓流经 PFO首例首例 PFO伴血栓形成报道于伴血栓形成报道于1876.既往通过超声心动图及术中见到嵌顿于既往通过超声心动图及术中见到嵌顿于PFO的血栓的血栓.但无法观察到小栓子的流程。但无法观察到小栓子的流程。服用阿司匹林的PFO患者脑血管事件/TIA复发率较高Mas et al.NE
4、JM 2019;345:1740-6.581 名患者有隐匿性脑卒中均接受阿司匹林治疗华法林阿司匹林复发性脑卒中研究Mohr et al.NEJM 2019;345:1444-51.N=2206 缺血性脑血管事件(56%腔梗;25%隐匿性;13%大血管性)随机接受阿司匹林325mg 或华法林治疗结论结论:抗血小板及抗凝治疗有效（无效）率相当。药物治疗 vs.PFO封堵术 Windecker et al.JACC 2019;44:750-8.308名 隐匿性脑卒中伴PFO患者随机接受药物治疗或PFO封堵术治疗药物治疗 vs.PFO 封堵术:观察性研究的荟萃分析Khairy et al.Ann In
5、t Med 2019;139:753-60.药物治疗(6 个研究)N=8953.8-12.0%4.9PFO封堵术(10 个研究)N=13550-4.9%3.01年脑卒中年脑卒中/TIA复发率复发率死亡死亡/脑卒中脑卒中/TIA事件事件/100 人年人年PFO 封堵器PFOASDAmplatzer PFOSTARFlexAmplatzer ASOCardioSEALHelexAmplatzerCribiform ASD左房伞植入左房伞植入右房伞植入右房伞植入植入前植入前植入后植入后偏头痛与PFO的关系12人口患有偏头痛(女性18%;男性6%)偏头痛患者中 存在PFO的占：48%的偏头痛伴视觉先兆
6、 123%的偏头痛不伴视觉先兆20%正常人隐匿性脑卒中伴PFO患者中偏头痛发生率52%有偏头痛伴视觉先兆271%封堵术后症状缓解3偏头痛患者较正常人MRI检查病变阳性率高13倍4Anzola.Neurology 2019;52:1622-5.Sztajzel.CV Diseases 2019;13:102-6.Wilmshurst.Lancet 2000;356:1648-51.Kruit.JAMA 2019;294:427-34.卵圆孔未闭与偏头痛之间可能的病理生理相关性经过PFO的微小栓子可引起偏头痛.体液因子（如5HT)免受肺降解,引起偏头痛.MIST研究结果Dowson A,et al
7、.Circulation 2019;117:1397-404.无偏头痛发作患者,n03131.0偏头痛发作频率/月,meanSD4.822.443.231.804.512.173.532.130.14 MIDAS总评分,median(range)36(3108)17(0270)34(2189)18(0240)0.88 头痛天数/3月 (MIDAS),median(range)27(070)18(090)30(580)21(080)0.79 HIT-6总评分,meanSD67.24.759.59.366.25.158.58.60.77 术前术前术后术后P value手术组手术组(n=74)假手术
8、组假手术组(n=73)偏头痛随机临床试验NMT Medical closed MIST II(January 24,2019).PREMIUM(AGA Medical)及 ESCAPE(St Jude Medical)仍在进行中.PFO 封堵器技术现况与展望目前封堵器技术的局限性大型，永久性植入物.远期并发症：心率失常，炎症，糜烂，血栓形成，过敏反应.未来的封堵器技术小型封堵器.生物可吸收(BioSTAR).可缝合封堵器.射频消融.Mullen et al.Circulation 2019;114:1962-7.结论目前隐匿性脑卒中的药物治疗疗效欠佳.研究提示存在高危复发脑卒中的亚组.尚无随机
9、临床试验支持任何药物治疗经皮 PFO封堵术可能成为隐匿性脑卒中预防的主要干预手段.安全.非随机临床试验资料提示对可有效预防脑卒中.有待关于脑卒中与偏头痛的进一步临床研究结果.结论Patent Foramen Ovale Closure:Controversies and Accomplishments May 9,2009Andrew D.Michaels,MD,MAS,FACC,FAHADirector,Cardiac Catheterization Laboratory and Interventional CardiologyUniversity of Utah,Salt Lake Ci
10、ty,UtahFetal CirculationDuring fetal life,oxygenated bloodreturning from the umbilical veinenters the RA through the IVC.Blood flow is directed by theEustachian valve from the IVCto the fossa ovalis and through the PFO.Post-Natal Septal DevelopmentIn UteroAfter BirthHagen,Scholz.Mayo Clin Proc 1984;
11、59:17-20.75%of Population 25%of PopulationClinical Syndromes Associated with PFOPlatypnea orthodeoxiaDecompression sickness/high-altitude pulmonary edemaCVA/TIAMigrainePlatypnoea OrthodeoxiaUncommon syndromeDyspnea induced by upright posture,with associated hypoxemiaMechanism:right-to-left interatri
12、al shuntingAigner et al.Eur J Cardiothor Surg 2019;33:268.Medina et al.Circulation 2019;104:741.Platypnea Orthodeoxia100 cases in literature since 1949PFO associated with:Aortic aneurysmChest deformityPost-pneumonectomy50 have undergone device closureDecompression Sickness230 asymptomatic divers sur
13、veyed27%had a PFODecompression chamber required:19%with a PFO2%without a PFOTorti et al.Eur Heart J 2019;25:1014-20.Cryptogenic Stroke Case40 yo man with sudden aphasia.No medical history.No obvious cause of stroke.TEE:atrial septal aneurysm and PFO.Associations:50%of people with cryptogenic stroke
14、have a PFO.Presumed mechanism:Paradoxical embolism of venous thrombus.In-situ thrombosis within PFO tunnel with embolization.Thrombus in transit through PFOFirst case of PFO with thrombus described in 1876.Thrombus caught in PFO has been seen by echo and at surgery.However,passages of small emboli a
15、re impossible to prove.Higher CVA/TIA Recurrence Rate in Patients with PFO+ASAMas et al.NEJM 2019;345:1740-6.581 patients with cryptogenic strokeAll treated with aspirinWarfarin-Aspirin Recurrent Stroke StudyMohr et al.NEJM 2019;345:1444-51.N=2206 with ischemic CVA(56%lacunar;25%cryptogenic;13%large
16、 vessel)Randomized to ASA 325mg vs WarfarinConclusion:Antiplatelet and anticoagulant therapy equally(in)effectiveMedical Therapy vs.PFO ClosureWindecker et al.JACC 2019;44:750-8.N=308 with cryptogenic CVA and PFORandomized to medical therapy or PFO closureMedical Therapy vs.PFO Closure:Meta-Analysis
17、 of Observational StudiesKhairy et al.Ann Int Med 2019;139:753-60.Medical Therapy(6 studies)N=8953.8-12.0%4.9PFO Closure(10 studies)N=13550-4.9%3.0Recurrent CVA/TIA1-YearDeath/CVA/TIAEvents/100 pt yrsPFO DevicesPFOASDAmplatzer PFOSTARFlexAmplatzer ASOCardioSEALHelexAmplatzerCribiform ASDLeft Atrial
18、Disc DeploymentRight Atrial Disc DeploymentPrePostAssociation Between Migraine and PFOMigraine headache affects 12%of population(18%F;6%M)Incidence of PFO in patients with migraine48%if migraine with aura123%if migraine without aura20%in controlsIncidence of migraine in cryptogenic stroke with PFO52
19、%had migraine with aura271%had suppression post-closure3Migraine patients have 13 times higher incidence of MRI lesions4Anzola.Neurology 2019;52:1622-5.Sztajzel.CV Diseases 2019;13:102-6.Wilmshurst.Lancet 2000;356:1648-51.Kruit.JAMA 2019;294:427-34.Potential Pathophysiologic Association Between PFO
20、and MigraineMicroembolism through PFO triggers migraine.Humoral factors(i.e.,serotonin)escape pulmonary degradation,triggering migraine.Published MIST ResultsDowson A,et al.Circulation 2019;117:1397-404.Patients with no migraine attacks,n03131.0Frequency of migraine attacks/mo,meanSD4.822.443.231.80
21、4.512.173.532.130.14 Total MIDAS score,median(range)36(3108)17(0270)34(2189)18(0240)0.88 Headache d/3 mo(MIDAS),median(range)27(070)18(090)30(580)21(080)0.79 HIT-6 total score,meanSD67.24.759.59.366.25.158.58.60.77 BaselineBaselinePostPostP valueImplant(n=74)Sham(n=73)Migraine Randomized Clinical Tr
22、ialsNMT Medical closed MIST II(January 24,2019).PREMIUM(AGA Medical)and ESCAPE(St Jude Medical)still enrolling.Current and Future PFO Device TechnologiesLimitations of Current Device TechnologiesLarge,permanent implants.Late complications:arrhythmia,inflammation,erosions,thrombus,allergic reactions.
23、Future Device TechnologiesSmaller profile devices.Bioabsorbable(BioSTAR).Suture-based devices.Radiofrequency ablation.Mullen et al.Circulation 2019;114:1962-7.Current medical therapy insufficient for patients with cryptogenic stroke.Subgroups at high-risk for recurrent CVA are identifiable.No RCT data in support of any treatment.Percutaneous PFO closure is likely to become a cornerstone of cryptogenic CVA prevention.Safe.Non-randomized data suggests efficacy for CVA prevention.Await clinical trial results for CVA and migraine.Conclusions
